Tubular System

Physiology Overview

Anatomy

The tubular system consists of:

• Proximal tubule (PT):
  • Proximal convoluted tubule Proximal convoluted tubule The renal tubule portion that extends from the bowman capsule in the kidney cortex into the kidney medulla. The proximal tubule consists of a convoluted proximal segment in the cortex, and a distal straight segment descending into the medulla where it forms the u-shaped loop of henle. Osmotic Diuretics
  • Proximal straight tubule (PST)
• Loop of Henle:
  • Thin descending limb
  • Thin ascending limb
  • Thick ascending limb Thick ascending limb Renal Sodium and Water Regulation
• Distal convoluted tubule Distal convoluted tubule The portion of renal tubule that begins from the enlarged segment of the ascending limb of the loop of henle. It reenters the kidney cortex and forms the convoluted segments of the distal tubule. Gitelman Syndrome
• Collecting ducts

Pathways of epithelial solute transport

• Paracellular Paracellular Renal Potassium Regulation: passive transport Passive transport The passive movement of molecules exceeding the rate expected by simple diffusion. No energy is expended in the process. It is achieved by the introduction of passively diffusing molecules to an environment or path that is more favorable to the movement of those molecules. Examples of facilitated diffusion are passive transport of hydrophilic substances across a lipid membrane through hydrophilic pores that traverse the membrane, and the sliding of a DNA binding protein along a strand of DNA. The Cell: Cell Membrane in between cells
• Transcellular: transport through cells; may be active or passive

Sodium Sodium A member of the alkali group of metals. It has the atomic symbol na, atomic number 11, and atomic weight 23. Hyponatremia/ Potassium Potassium An element in the alkali group of metals with an atomic symbol k, atomic number 19, and atomic weight 39. 10. It is the chief cation in the intracellular fluid of muscle and other cells. Potassium ion is a strong electrolyte that plays a significant role in the regulation of fluid volume and maintenance of the water-electrolyte balance. Hyperkalemia ATPase

• Located on the basolateral side of tubule cells
• Transports:
  • 3 Na⁺ out of the cell
  • 2 K⁺ into the cell
• Creates a Na⁺ concentration gradient and a voltage gradient:
  • The tubule lumen becomes electronegative in the early proximal convoluted tubule Proximal convoluted tubule The renal tubule portion that extends from the bowman capsule in the kidney cortex into the kidney medulla. The proximal tubule consists of a convoluted proximal segment in the cortex, and a distal straight segment descending into the medulla where it forms the u-shaped loop of henle. Osmotic Diuretics (however, the electronegativity changes as substances are absorbed throughout the nephron Nephron The functional units of the kidney, consisting of the glomerulus and the attached tubule. Kidneys: Anatomy).
  • Active and passive transport Passive transport The passive movement of molecules exceeding the rate expected by simple diffusion. No energy is expended in the process. It is achieved by the introduction of passively diffusing molecules to an environment or path that is more favorable to the movement of those molecules. Examples of facilitated diffusion are passive transport of hydrophilic substances across a lipid membrane through hydrophilic pores that traverse the membrane, and the sliding of a DNA binding protein along a strand of DNA. The Cell: Cell Membrane mechanisms are dependent on these gradients.

Methods of water transport

• Paracellular Paracellular Renal Potassium Regulation:
  • Water moves through the epithelial tight junctions Tight junctions Cell-cell junctions that seal adjacent epithelial cells together, preventing the passage of most dissolved molecules from one side of the epithelial sheet to the other. The Cell: Cell Junctions (“leaky” subtype of tight junctions Tight junctions Cell-cell junctions that seal adjacent epithelial cells together, preventing the passage of most dissolved molecules from one side of the epithelial sheet to the other. The Cell: Cell Junctions).
  • Movement of water is dictated by osmolarity Osmolarity The concentration of osmotically active particles in solution expressed in terms of osmoles of solute per liter of solution. Osmolality is expressed in terms of osmoles of solute per kilogram of solvent. Hypernatremia ( osmosis Osmosis Tendency of fluids (e.g., water) to move from the less concentrated to the more concentrated side of a semipermeable membrane. Body Fluid Compartments).
• Transcellular: 
  • Water moves through the cell via specific channels Channels The Cell: Cell Membrane known as aquaporins.
  • Aquaporins are located in:
    • PT
    • Thin descending limb of the loop of Henle
    • Collecting duct Collecting duct Straight tubes commencing in the radiate part of the kidney cortex where they receive the curved ends of the distal convoluted tubules. In the medulla the collecting tubules of each pyramid converge to join a central tube (duct of bellini) which opens on the summit of the papilla. Renal Cell Carcinoma
• Solvent drag:
  • Some solutes are “dragged” along as water moves.
  • Solutes move via convective currents created by the movement of water.

Transport maximums

• The reabsorption capacity for any given substance is limited.
• Once exceeded, additional substances are lost in the urine.
• Also referred to as the “renal threshold Threshold Minimum voltage necessary to generate an action potential (an all-or-none response) Skeletal Muscle Contraction” for reabsorption
• For example, glucose Glucose A primary source of energy for living organisms. It is naturally occurring and is found in fruits and other parts of plants in its free state. It is used therapeutically in fluid and nutrient replacement. Lactose Intolerance:
  • Has transport maximum (T_m) of 375 mg/min
  • At this rate, the kidneys Kidneys The kidneys are a pair of bean-shaped organs located retroperitoneally against the posterior wall of the abdomen on either side of the spine. As part of the urinary tract, the kidneys are responsible for blood filtration and excretion of water-soluble waste in the urine. Kidneys: Anatomy can reabsorb 100% of the filtered glucose Glucose A primary source of energy for living organisms. It is naturally occurring and is found in fruits and other parts of plants in its free state. It is used therapeutically in fluid and nutrient replacement. Lactose Intolerance up to a plasma Plasma The residual portion of blood that is left after removal of blood cells by centrifugation without prior blood coagulation. Transfusion Products glucose Glucose A primary source of energy for living organisms. It is naturally occurring and is found in fruits and other parts of plants in its free state. It is used therapeutically in fluid and nutrient replacement. Lactose Intolerance concentration of approximately 180 mg/dL.
  • When plasma Plasma The residual portion of blood that is left after removal of blood cells by centrifugation without prior blood coagulation. Transfusion Products glucose Glucose A primary source of energy for living organisms. It is naturally occurring and is found in fruits and other parts of plants in its free state. It is used therapeutically in fluid and nutrient replacement. Lactose Intolerance exceeds 180 mg/dL:
    • Kidneys Kidneys The kidneys are a pair of bean-shaped organs located retroperitoneally against the posterior wall of the abdomen on either side of the spine. As part of the urinary tract, the kidneys are responsible for blood filtration and excretion of water-soluble waste in the urine. Kidneys: Anatomy are no longer capable of reabsorbing 100% of the filtered glucose Glucose A primary source of energy for living organisms. It is naturally occurring and is found in fruits and other parts of plants in its free state. It is used therapeutically in fluid and nutrient replacement. Lactose Intolerance.
    • Excess glucose Glucose A primary source of energy for living organisms. It is naturally occurring and is found in fruits and other parts of plants in its free state. It is used therapeutically in fluid and nutrient replacement. Lactose Intolerance is lost in urine (“ glucosuria Glucosuria Diabetes Mellitus”).

Peritubular capillary absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption

Peritubular capillary reabsorption differs from regular Regular Insulin capillary reabsorption to maximize the reabsorption of substances back into the bloodstream.

• Regular Regular Insulin capillaries Capillaries Capillaries are the primary structures in the circulatory system that allow the exchange of gas, nutrients, and other materials between the blood and the extracellular fluid (ECF). Capillaries are the smallest of the blood vessels. Because a capillary diameter is so small, only 1 RBC may pass through at a time. Capillaries: Histology filter along their 1st half and reabsorb along their 2nd half:
  • Arterial half: higher capillary hydrostatic pressure Hydrostatic pressure The pressure due to the weight of fluid. Edema and lower oncotic pressure Oncotic Pressure Edema → filtration
  • Venous half: lower capillary hydrostatic pressure Hydrostatic pressure The pressure due to the weight of fluid. Edema and higher oncotic pressure Oncotic Pressure Edema → reabsorption
• Peritubular capillaries Peritubular capillaries Glomerular Filtration reabsorb fluid across their entire length:
  • Lower capillary hydrostatic pressure Hydrostatic pressure The pressure due to the weight of fluid. Edema and higher capillary oncotic pressure Oncotic Pressure Edema across their entire length
  • No area of filtration

Proximal Tubule: Reabsorption of Ions

Glomerular filtration Glomerular filtration The kidneys are primarily in charge of the maintenance of water and solute homeostasis through the processes of filtration, reabsorption, secretion, and excretion. Glomerular filtration is the process of converting the systemic blood supply into a filtrate, which will ultimately become the urine. Glomerular Filtration is a very nonspecific process, resulting in the filtration of large quantities of important substances that the body needs to retain (e.g., Na⁺, HCO₃^–). The primary function of the PT is to reabsorb as much of these substances as possible. Subsequently, the other nephron Nephron The functional units of the kidney, consisting of the glomerulus and the attached tubule. Kidneys: Anatomy segments fine-tune the urine composition.

Anatomy of the PT

• Divided into 2 parts: proximal convoluted tubule Proximal convoluted tubule The renal tubule portion that extends from the bowman capsule in the kidney cortex into the kidney medulla. The proximal tubule consists of a convoluted proximal segment in the cortex, and a distal straight segment descending into the medulla where it forms the u-shaped loop of henle. Osmotic Diuretics and PST
  • Proximal convoluted tubule Proximal convoluted tubule The renal tubule portion that extends from the bowman capsule in the kidney cortex into the kidney medulla. The proximal tubule consists of a convoluted proximal segment in the cortex, and a distal straight segment descending into the medulla where it forms the u-shaped loop of henle. Osmotic Diuretics: primary location for PT reabsorption
  • PST: important for PT secretion Secretion Coagulation Studies
• Brush border cells line the tubule lumen to increase the surface area for reabsorption.
• Na⁺/K⁺-ATPase is located on the basolateral side of the epithelial cells.

Sodium Sodium A member of the alkali group of metals. It has the atomic symbol na, atomic number 11, and atomic weight 23. Hyponatremia reabsorption in the PT

• Coupled with reabsorption of other substances via cotransporters:
  • Glucose Glucose A primary source of energy for living organisms. It is naturally occurring and is found in fruits and other parts of plants in its free state. It is used therapeutically in fluid and nutrient replacement. Lactose Intolerance
  • Amino acids Amino acids Organic compounds that generally contain an amino (-NH2) and a carboxyl (-COOH) group. Twenty alpha-amino acids are the subunits which are polymerized to form proteins. Basics of Amino Acids
  • Phosphate Phosphate Inorganic salts of phosphoric acid. Electrolytes
  • Organic acids Acids Chemical compounds which yield hydrogen ions or protons when dissolved in water, whose hydrogen can be replaced by metals or basic radicals, or which react with bases to form salts and water (neutralization). An extension of the term includes substances dissolved in media other than water. Acid-Base Balance
• Powered by the Na⁺ gradient generated by the basolateral Na⁺/K⁺-ATPase:
  • Low intracellular Na⁺ concentration
  • High Na⁺ concentration in the tubule lumen and interstitial space on the basolateral side
• Na⁺ reabsorption drives the paracellular Paracellular Renal Potassium Regulation reabsorption of water:
  • Na⁺ and water are reabsorbed at the same rate.
  • Reabsorption of Na⁺ in the PT is isotonic Isotonic Solutions having the same osmotic pressure as blood serum, or another solution with which they are compared. Renal Sodium and Water Regulation to plasma Plasma The residual portion of blood that is left after removal of blood cells by centrifugation without prior blood coagulation. Transfusion Products.
• Efficiency: Approximately ⅔ of filtered water and Na⁺ are reabsorbed in the PT.

Chloride Chloride Inorganic compounds derived from hydrochloric acid that contain the Cl- ion. Electrolytes (Cl^–) reabsorption in the PT

• Majority of the filtered Cl^– is reabsorbed in the PT.
• Transport is primarily paracellular Paracellular Renal Potassium Regulation.
• Powered by the voltage gradient in the early PT generated by Na⁺/K⁺-ATPase:
  • Cl^– is repelled by the electronegative tubule lumen.
  • Cl^– is attracted to the electropositive basolateral interstitium.

Potassium Potassium An element in the alkali group of metals with an atomic symbol k, atomic number 19, and atomic weight 39. 10. It is the chief cation in the intracellular fluid of muscle and other cells. Potassium ion is a strong electrolyte that plays a significant role in the regulation of fluid volume and maintenance of the water-electrolyte balance. Hyperkalemia, calcium Calcium A basic element found in nearly all tissues. It is a member of the alkaline earth family of metals with the atomic symbol ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in many enzymatic processes. Electrolytes ( Ca CA Condylomata acuminata are a clinical manifestation of genital HPV infection. Condylomata acuminata are described as raised, pearly, flesh-colored, papular, cauliflower-like lesions seen in the anogenital region that may cause itching, pain, or bleeding. Condylomata Acuminata (Genital Warts)²⁺), and magnesium Magnesium A metallic element that has the atomic symbol mg, atomic number 12, and atomic weight 24. 31. It is important for the activity of many enzymes, especially those involved in oxidative phosphorylation. Electrolytes (Mg²⁺) reabsorption in the PT

• Early PT: paracellular Paracellular Renal Potassium Regulation reabsorption via solvent drag
• Late PT: paracellular Paracellular Renal Potassium Regulation via voltage gradient 
  • Due to upstream reabsorption of Cl^– in the early PT, the polarity in the late PT flips.
  • In the late PT, the tubule lumen becomes more electropositive, and the basolateral interstitium becomes more electronegative.
• Efficiency: 
  • 80% of the filtered K⁺ is reabsorbed in the PT.
  • 65% of the filtered Ca CA Condylomata acuminata are a clinical manifestation of genital HPV infection. Condylomata acuminata are described as raised, pearly, flesh-colored, papular, cauliflower-like lesions seen in the anogenital region that may cause itching, pain, or bleeding. Condylomata Acuminata (Genital Warts)²⁺ is reabsorbed in the PT.
  • 15% of the filtered Mg²⁺ is reabsorbed in the PT.

Bicarbonate reabsorption Bicarbonate reabsorption Acid-Base Balance in the PT

Reabsorption of HCO₃^– requires a more complex mechanism:

• Sodium-hydrogen ion exchanger 3 ( NHE3 NHE3 A sodium-hydrogen antiporter expressed primarily by epithelial cells in the kidneys, it localizes to the apical membrane of the proximal kidney tubule, where it functions in sodium and water reabsorption and possibly calcium homeostasis. It also is expressed in heart, brain, and lung tissues and is resistant to amiloride inhibition. Carbonic Anhydrase Inhibitors) reabsorbs Na⁺ and secretes H⁺.
• The secreted H⁺ combines with the filtered HCO₃^– to form carbonic acid (H₂CO₃) in the tubular lumen.
• H₂CO₃ is converted to H₂O and CO₂ by apical carbonic anhydrase-IV Carbonic anhydrase-IV A carbonic anhydrase isoenzyme found in mitochondria where it provides bicarbonate ions that are components in the urea cycle and in gluconeogenesis. Carbonic Anhydrase Inhibitors. 
• CO₂ diffuses freely across the apical membrane back into the cell.
• Intracellular carbonic anhydrase-II Carbonic anhydrase-II A cytosolic carbonic anhydrase isoenzyme found widely distributed in cells of almost all tissues. Deficiencies of carbonic anhydrase II produce a syndrome characterized by osteopetrosis, renal tubular acidosis and cerebral calcification. Carbonic Anhydrase Inhibitors converts CO₂ and H₂O back into H₂CO₃.
• H₂CO₃ then dissociates into H⁺ and HCO₃^–:
  • H⁺ is recycled through the process via secretion Secretion Coagulation Studies by NHE3 NHE3 A sodium-hydrogen antiporter expressed primarily by epithelial cells in the kidneys, it localizes to the apical membrane of the proximal kidney tubule, where it functions in sodium and water reabsorption and possibly calcium homeostasis. It also is expressed in heart, brain, and lung tissues and is resistant to amiloride inhibition. Carbonic Anhydrase Inhibitors.
  • HCO₃^– is absorbed through the basolateral membrane via:
    • Na⁺-HCO₃^– cotransporter 
    • HCO₃^–-Cl^– exchanger 
• Net effects of the entire process:
  • Excretion of H⁺
  • Absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption of HCO₃^– 
• Efficiency: Under normal circumstances, 80% of the filtered HCO₃^– is reabsorbed in the PT.

Phosphate Phosphate Inorganic salts of phosphoric acid. Electrolytes (PO₄^3-) reabsorption in the PT

• PO₄^3- reabsorption is regulated by the parathyroid Parathyroid The parathyroid glands are 2 pairs of small endocrine glands found in close proximity to the thyroid gland. The superior parathyroid glands are lodged within the parenchyma of the upper poles of the right and left thyroid lobes; the inferior parathyroid glands are close to the inferior tips or poles of the lobes. Parathyroid Glands: Anatomy hormone (PTH): PTH inhibits PO₄^3- reabsorption.
• ↓ PTH → ↑ PO₄^3- reabsorption:
  • In the setting of ↓ PTH, Na⁺/PO₄^3- cotransporters (transporting 3 Na⁺ and 1 PO₄^3-) are inserted into the apical membrane
  • PO₄^3- moves across the cell and is transported across the basolateral membrane via an unknown transporter.
• ↑ PTH → ↓ PO₄^3- reabsorption:
  • PTH binds to a basolateral PTH receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors of the PT cell.
  • Na+/PO₄^3- cotransporters are downregulated.

Proximal Tubule: Reabsorption of Macromolecules

Glucose Glucose A primary source of energy for living organisms. It is naturally occurring and is found in fruits and other parts of plants in its free state. It is used therapeutically in fluid and nutrient replacement. Lactose Intolerance reabsorption in the PT

• Apical transporters: sodium-glucose linked transporter (SGLT)2 and SGLT1
  • SGLT2 transporter:
    • 1 Na⁺ and 1 glucose Glucose A primary source of energy for living organisms. It is naturally occurring and is found in fruits and other parts of plants in its free state. It is used therapeutically in fluid and nutrient replacement. Lactose Intolerance move into the cell.
    • Responsible for the majority of glucose Glucose A primary source of energy for living organisms. It is naturally occurring and is found in fruits and other parts of plants in its free state. It is used therapeutically in fluid and nutrient replacement. Lactose Intolerance reabsorption in the PT
  • SGLT1 transporter:
    • 2 Na⁺ and 1 glucose Glucose A primary source of energy for living organisms. It is naturally occurring and is found in fruits and other parts of plants in its free state. It is used therapeutically in fluid and nutrient replacement. Lactose Intolerance move into the cell.
    • Responsible for reabsorbing glucose Glucose A primary source of energy for living organisms. It is naturally occurring and is found in fruits and other parts of plants in its free state. It is used therapeutically in fluid and nutrient replacement. Lactose Intolerance that is not captured by SGLT2
    • Lower capacity but higher affinity for glucose Glucose A primary source of energy for living organisms. It is naturally occurring and is found in fruits and other parts of plants in its free state. It is used therapeutically in fluid and nutrient replacement. Lactose Intolerance than SGLT2
  • Both are powered by the concentration gradient of Na⁺ created by the basolateral Na⁺/K⁺-ATPase.
• Basolateral transporters: glucose Glucose A primary source of energy for living organisms. It is naturally occurring and is found in fruits and other parts of plants in its free state. It is used therapeutically in fluid and nutrient replacement. Lactose Intolerance transporter (GLUT)2 and GLUT1
  • Glucose Glucose A primary source of energy for living organisms. It is naturally occurring and is found in fruits and other parts of plants in its free state. It is used therapeutically in fluid and nutrient replacement. Lactose Intolerance moves out of the cell and into the interstitium via the GLUT.
  • GLUT2 GLUT2 A glucose transport facilitator that is expressed primarily in pancreatic beta cells; liver; and kidneys. It may function as a glucose sensor to regulate insulin release and glucose homeostasis. Digestion and Absorption is paired with SGLT2, and GLUT1 is paired with SGLT1.
• Efficiency: Under normal circumstances, 100% of glucose Glucose A primary source of energy for living organisms. It is naturally occurring and is found in fruits and other parts of plants in its free state. It is used therapeutically in fluid and nutrient replacement. Lactose Intolerance is reabsorbed within the 1st 25% of the PT.

Peptide reabsorption in the PT

• Early PT apical proteins Proteins Linear polypeptides that are synthesized on ribosomes and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of amino acids determines the shape the polypeptide will take, during protein folding, and the function of the protein. Energy Homeostasis: 
  • PepT1: H⁺/peptide cotransporter responsible for the majority of peptide reabsorption in the PT
  • Peptidase: membrane-bound enzyme
    • Located in the early segment of the PT
    • Breaks down larger tripeptides within the tubule lumen
    • The smaller broken-down peptides can then enter via PepT1.
• Late PT apical proteins Proteins Linear polypeptides that are synthesized on ribosomes and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of amino acids determines the shape the polypeptide will take, during protein folding, and the function of the protein. Energy Homeostasis:
  • PepT2: H⁺/peptide cotransporter responsible for reabsorbing peptides not captured by PepT1
  • Megalin and cubilin receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors:
    • Bind BIND Hyperbilirubinemia of the Newborn and endocytose small proteins Proteins Linear polypeptides that are synthesized on ribosomes and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of amino acids determines the shape the polypeptide will take, during protein folding, and the function of the protein. Energy Homeostasis 
    • Endocytosed vacuoles bind BIND Hyperbilirubinemia of the Newborn to basolateral membrane and release contents.
• Peptides are digested into amino acids Amino acids Organic compounds that generally contain an amino (-NH2) and a carboxyl (-COOH) group. Twenty alpha-amino acids are the subunits which are polymerized to form proteins. Basics of Amino Acids by proteases Proteases Proteins and Peptides within the cell.
• Amino acids Amino acids Organic compounds that generally contain an amino (-NH2) and a carboxyl (-COOH) group. Twenty alpha-amino acids are the subunits which are polymerized to form proteins. Basics of Amino Acids exit the cell via transporters on the basolateral membrane.
• Efficiency:
  • 100% reabsorbed within the 1st 25% of the PT.
  • Renal threshold Threshold Minimum voltage necessary to generate an action potential (an all-or-none response) Skeletal Muscle Contraction for reabsorption can be exceeded → “overflow proteinuria Proteinuria The presence of proteins in the urine, an indicator of kidney diseases. Nephrotic Syndrome in Children”

Amino acid Amino acid Amino acids (AAs) are composed of a central carbon atom attached to a carboxyl group, an amino group, a hydrogen atom, and a side chain (R group). Basics of Amino Acids reabsorption

• Apical reabsorption: 
  • Anionic (acidic) or cationic (basic) amino acids Amino acids Organic compounds that generally contain an amino (-NH2) and a carboxyl (-COOH) group. Twenty alpha-amino acids are the subunits which are polymerized to form proteins. Basics of Amino Acids: various ion exchangers
  • Neutral amino acids Amino acids Organic compounds that generally contain an amino (-NH2) and a carboxyl (-COOH) group. Twenty alpha-amino acids are the subunits which are polymerized to form proteins. Basics of Amino Acids: via Na⁺ or H⁺ cotransport
• Basolateral reabsorption:
  • Aromatic amino acids Aromatic amino acids Amino acids containing an aromatic side chain. Basics of Amino Acids: via facilitated diffusion Diffusion The tendency of a gas or solute to pass from a point of higher pressure or concentration to a point of lower pressure or concentration and to distribute itself throughout the available space. Diffusion, especially facilitated diffusion, is a major mechanism of biological transport. Peritoneal Dialysis and Hemodialysis 
  • Cationic (basic) and neutral amino acids Amino acids Organic compounds that generally contain an amino (-NH2) and a carboxyl (-COOH) group. Twenty alpha-amino acids are the subunits which are polymerized to form proteins. Basics of Amino Acids: via Na⁺ cotransport

Proximal Tubule: Secretion

Secretion Secretion Coagulation Studies occurs primarily in the PST (i.e., late PT) and allows for the elimination Elimination The initial damage and destruction of tumor cells by innate and adaptive immunity. Completion of the phase means no cancer growth. Cancer Immunotherapy of endogenous and exogenous substances such as toxins and drugs.

Organic anions Anions Negatively charged atoms, radicals or groups of atoms which travel to the anode or positive pole during electrolysis. Electrolytes

• Organic anions Anions Negatively charged atoms, radicals or groups of atoms which travel to the anode or positive pole during electrolysis. Electrolytes ( OA OA Osteoarthritis (OA) is the most common form of arthritis, and is due to cartilage destruction and changes of the subchondral bone. The risk of developing this disorder increases with age, obesity, and repetitive joint use or trauma. Patients develop gradual joint pain, stiffness lasting < 30 minutes, and decreased range of motion. Osteoarthritis^–s) are moved from the basolateral side into cells by organic anion transporters (OATs).
• Transported into the tubule lumen by 2 proteins Proteins Linear polypeptides that are synthesized on ribosomes and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of amino acids determines the shape the polypeptide will take, during protein folding, and the function of the protein. Energy Homeostasis:
  • Multidrug-resistant transporter (MRP2)
  • OAT4 exchanger
• Examples of OA OA Osteoarthritis (OA) is the most common form of arthritis, and is due to cartilage destruction and changes of the subchondral bone. The risk of developing this disorder increases with age, obesity, and repetitive joint use or trauma. Patients develop gradual joint pain, stiffness lasting < 30 minutes, and decreased range of motion. Osteoarthritis^–s secreted in the PT: bile Bile An emulsifying agent produced in the liver and secreted into the duodenum. Its composition includes bile acids and salts; cholesterol; and electrolytes. It aids digestion of fats in the duodenum. Gallbladder and Biliary Tract: Anatomy salts, urate, certain drugs (see table below)

Organic cations Cations Positively charged atoms, radicals or groups of atoms which travel to the cathode or negative pole during electrolysis. Electrolytes

• Organic cations Cations Positively charged atoms, radicals or groups of atoms which travel to the cathode or negative pole during electrolysis. Electrolytes (OC⁺s) are moved from the basolateral side into cells by organic cation transporters (OCTs).
• Transported into the tubule lumen by 2 proteins Proteins Linear polypeptides that are synthesized on ribosomes and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of amino acids determines the shape the polypeptide will take, during protein folding, and the function of the protein. Energy Homeostasis:
  • Multidrug-resistant transporter (MDR1) 
  • Organic cation transporter novel (OCTN) exchanger 
• Examples: creatinine, dopamine Dopamine One of the catecholamine neurotransmitters in the brain. It is derived from tyrosine and is the precursor to norepinephrine and epinephrine. Dopamine is a major transmitter in the extrapyramidal system of the brain, and important in regulating movement. Receptors and Neurotransmitters of the CNS, certain drugs (see table below)

Organic ions secreted by the PT

Loop of Henle

The loop of Henle is a complex segment of the nephron Nephron The functional units of the kidney, consisting of the glomerulus and the attached tubule. Kidneys: Anatomy with 2 main purposes: maintaining the corticomedullary gradient and reabsorbing moderate amounts of Na⁺ and water. These 2 processes are linked via the countercurrent multiplier system in the thin loops, and additional Na⁺ absorption Absorption Absorption involves the uptake of nutrient molecules and their transfer from the lumen of the GI tract across the enterocytes and into the interstitial space, where they can be taken up in the venous or lymphatic circulation. Digestion and Absorption occurs via active transport Active transport The movement of materials across cell membranes and epithelial layers against an electrochemical gradient, requiring the expenditure of metabolic energy. The Cell: Cell Membrane in the thick ascending limb Thick ascending limb Renal Sodium and Water Regulation.

Anatomy of the loop of Henle

• Descending thin limb 
• Hairpin turn
• Ascending thin limb
• Thick ascending limb Thick ascending limb Renal Sodium and Water Regulation

Corticomedullary gradient

• Osmolality Osmolality Plasma osmolality refers to the combined concentration of all solutes in the blood. Renal Sodium and Water Regulation of the renal interstitium ranges from approximately 300 mOsm/kg in the cortex to approximately 1200 mOsm/kg in the inner medulla.
• This gradient is necessary for dynamic control of water reabsorption later in the collecting duct Collecting duct Straight tubes commencing in the radiate part of the kidney cortex where they receive the curved ends of the distal convoluted tubules. In the medulla the collecting tubules of each pyramid converge to join a central tube (duct of bellini) which opens on the summit of the papilla. Renal Cell Carcinoma. 
• The gradient is established and maintained by the passive movement of fluid and solutes according to the countercurrent multiplier theory.

Countercurrent multiplier theory

The countercurrent multiplier theory explains how the movement of fluids and solutes creates a significant corticomedullary gradient. This process occurs primarily in the thin loops of Henle and via urea Urea A compound formed in the liver from ammonia produced by the deamination of amino acids. It is the principal end product of protein catabolism and constitutes about one half of the total urinary solids. Urea Cycle recycling.

Within the thin loops of Henle:

• Thin descending limb:
  • Permeable only to water and not to solutes
  • Increasing amounts of water exit the tubules as the tubule fluid descends through areas of the interstitium with increasingly high osmolality Osmolality Plasma osmolality refers to the combined concentration of all solutes in the blood. Renal Sodium and Water Regulation (known as “fluid displacement Displacement The process by which an emotional or behavioral response that is appropriate for one situation appears in another situation for which it is inappropriate. Defense Mechanisms”).
  • Tubule fluid becomes concentrated.
• Thin ascending limb:
  • Permeable only to solutes (via passive transport Passive transport The passive movement of molecules exceeding the rate expected by simple diffusion. No energy is expended in the process. It is achieved by the introduction of passively diffusing molecules to an environment or path that is more favorable to the movement of those molecules. Examples of facilitated diffusion are passive transport of hydrophilic substances across a lipid membrane through hydrophilic pores that traverse the membrane, and the sliding of a DNA binding protein along a strand of DNA. The Cell: Cell Membrane) and not to water
  • Increasing amounts of solutes exit the tubule as the tubule fluid ascends through areas of the interstitium with decreasing osmolality Osmolality Plasma osmolality refers to the combined concentration of all solutes in the blood. Renal Sodium and Water Regulation (known as a “single effect”).
  • Tubule fluid becomes near isotonic Isotonic Solutions having the same osmotic pressure as blood serum, or another solution with which they are compared. Renal Sodium and Water Regulation again at the end of the thin ascending limb.
• Repeating “fluid displacement Displacement The process by which an emotional or behavioral response that is appropriate for one situation appears in another situation for which it is inappropriate. Defense Mechanisms” followed by a “single effect” over and over again generates and maintains the corticomedullary gradient.

Urea Urea A compound formed in the liver from ammonia produced by the deamination of amino acids. It is the principal end product of protein catabolism and constitutes about one half of the total urinary solids. Urea Cycle recycling:

• In the PT: Approximately 50% of urea Urea A compound formed in the liver from ammonia produced by the deamination of amino acids. It is the principal end product of protein catabolism and constitutes about one half of the total urinary solids. Urea Cycle is reabsorbed via paracellular Paracellular Renal Potassium Regulation transport.
• In the loop of Henle:
  • Approximately 50% of urea Urea A compound formed in the liver from ammonia produced by the deamination of amino acids. It is the principal end product of protein catabolism and constitutes about one half of the total urinary solids. Urea Cycle reenters the tubule (passive secretion Secretion Coagulation Studies).
  • Approximately 30% is reabsorbed.
• In the collecting duct Collecting duct Straight tubes commencing in the radiate part of the kidney cortex where they receive the curved ends of the distal convoluted tubules. In the medulla the collecting tubules of each pyramid converge to join a central tube (duct of bellini) which opens on the summit of the papilla. Renal Cell Carcinoma:
  • Approximately 50% of urea Urea A compound formed in the liver from ammonia produced by the deamination of amino acids. It is the principal end product of protein catabolism and constitutes about one half of the total urinary solids. Urea Cycle is reabsorbed via the apical transporter UT-A1 and the basolateral transporter UT.
  • Antidiuretic hormone Antidiuretic hormone Antidiuretic hormones released by the neurohypophysis of all vertebrates (structure varies with species) to regulate water balance and osmolarity. In general, vasopressin is a nonapeptide consisting of a six-amino-acid ring with a cysteine 1 to cysteine 6 disulfide bridge or an octapeptide containing a cystine. All mammals have arginine vasopressin except the pig with a lysine at position 8. Vasopressin, a vasoconstrictor, acts on the kidney collecting ducts to increase water reabsorption, increase blood volume and blood pressure. Hypernatremia (ADH) upregulates apical UT-A1 → ↑ urea Urea A compound formed in the liver from ammonia produced by the deamination of amino acids. It is the principal end product of protein catabolism and constitutes about one half of the total urinary solids. Urea Cycle reabsorption
• Reabsorbed urea Urea A compound formed in the liver from ammonia produced by the deamination of amino acids. It is the principal end product of protein catabolism and constitutes about one half of the total urinary solids. Urea Cycle in the interstitium contributes to the corticomedullary gradient.
• Ultimately, 60% of filtered urea Urea A compound formed in the liver from ammonia produced by the deamination of amino acids. It is the principal end product of protein catabolism and constitutes about one half of the total urinary solids. Urea Cycle is retained for this purpose and 40% is excreted.

Thick ascending limb Thick ascending limb Renal Sodium and Water Regulation

The Na-K-2Cl ( NKCC2 NKCC2 Renal Potassium Regulation) cotransporter is the key transport protein in the thick ascending limb Thick ascending limb Renal Sodium and Water Regulation.

• NKCC2 NKCC2 Renal Potassium Regulation transports the following into the cell from the tubule lumen:
  • 1 Na⁺ (exits basolateral side via Na⁺/K⁺-ATPase)
  • 1 K⁺ (can exit on the apical and/or basolateral side via the ROMK channel ROMK channel Renal Potassium Regulation)
  • 2 Cl^– (exit basolateral side via Cl^– channels Channels The Cell: Cell Membrane, primarily the ClC-Kb channel)
• Generates an electrical gradient Electrical gradient Renal Potassium Regulation: net effect of NKCC2 NKCC2 Renal Potassium Regulation is 2 Cl- and 1 Na+ on the basolateral side:
  • K⁺ is recycled into the tubular fluid via ROMK channels Channels The Cell: Cell Membrane (to facilitate further NKCC2 NKCC2 Renal Potassium Regulation function).
  • The basolateral side becomes more electronegative due to unmatched Cl^–.
  • Important for driving the paracellular Paracellular Renal Potassium Regulation transport of cations Cations Positively charged atoms, radicals or groups of atoms which travel to the cathode or negative pole during electrolysis. Electrolytes 
• Contributes to the osmotic gradient between tubular fluid and interstitium:
  • Water does not follow solutes (Na⁺, K⁺, Cl^–) into the interstitium.
  • Tubule fluid (i.e., urine) becomes hypotonic Hypotonic Solutions that have a lesser osmotic pressure than a reference solution such as blood, plasma, or interstitial fluid. Renal Sodium and Water Regulation to plasma Plasma The residual portion of blood that is left after removal of blood cells by centrifugation without prior blood coagulation. Transfusion Products (“ diluting segment Diluting segment Renal Sodium and Water Regulation”).
• Site of action for loop diuretics Diuretics Agents that promote the excretion of urine through their effects on kidney function. Heart Failure and Angina Medication ( furosemide Furosemide A benzoic-sulfonamide-furan. It is a diuretic with fast onset and short duration that is used for edema and chronic renal insufficiency. Loop Diuretics, torsemide Torsemide A pyridine and sulfonamide derivative that acts as a sodium-potassium chloride symporter inhibitor. It is used for the treatment of edema associated with congestive heart failure; chronic renal insufficiency; and liver diseases. It is also used for the management of hypertension. Loop Diuretics, bumetanide Bumetanide A sulfamyl diuretic. Loop Diuretics):
  • Inhibit NKCC2 NKCC2 Renal Potassium Regulation → more Na⁺, K⁺, and Cl^– remain in the lumen
  • Increased Na⁺ in tubule lumen obligates water to stay with it → both are excreted

Distal Convoluted Tubule

The distal convoluted tubule Distal convoluted tubule The portion of renal tubule that begins from the enlarged segment of the ascending limb of the loop of henle. It reenters the kidney cortex and forms the convoluted segments of the distal tubule. Gitelman Syndrome (DCT) is another “ diluting segment Diluting segment Renal Sodium and Water Regulation” of the nephron Nephron The functional units of the kidney, consisting of the glomerulus and the attached tubule. Kidneys: Anatomy, where the thiazide-sensitive NaCl cotransporter helps generate hypotonic Hypotonic Solutions that have a lesser osmotic pressure than a reference solution such as blood, plasma, or interstitial fluid. Renal Sodium and Water Regulation tubule fluid due to the DCT not being permeable to water. The transport of K⁺, Mg⁺², and Ca CA Condylomata acuminata are a clinical manifestation of genital HPV infection. Condylomata acuminata are described as raised, pearly, flesh-colored, papular, cauliflower-like lesions seen in the anogenital region that may cause itching, pain, or bleeding. Condylomata Acuminata (Genital Warts)²⁺ also occurs in this segment.

Calcium Calcium A basic element found in nearly all tissues. It is a member of the alkaline earth family of metals with the atomic symbol ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in many enzymatic processes. Electrolytes reabsorption

• Reabsorbed via apical TRPV5 channels Channels The Cell: Cell Membrane:
  • TRPV5 is upregulated by the action of PTH.
  • ↑ PTH → ↑ adenylyl cyclase and phospholipase C Phospholipase C A subclass of phospholipases that hydrolyze the phosphoester bond found in the third position of glycerophospholipids. Although the singular term phospholipase C specifically refers to an enzyme that catalyzes the hydrolysis of phosphatidylcholine, it is commonly used in the literature to refer to broad variety of enzymes that specifically catalyze the hydrolysis of phosphatidylinositols. Pseudomonas → ↑ phosphorylation Phosphorylation The introduction of a phosphoryl group into a compound through the formation of an ester bond between the compound and a phosphorus moiety. Post-translational Protein Processing of TRPV5 → ↑ open probability Probability Probability is a mathematical tool used to study randomness and provide predictions about the likelihood of something happening. There are several basic rules of probability that can be used to help determine the probability of multiple events happening together, separately, or sequentially. Basics of Probability of TRPV5 channel → ↑ Ca CA Condylomata acuminata are a clinical manifestation of genital HPV infection. Condylomata acuminata are described as raised, pearly, flesh-colored, papular, cauliflower-like lesions seen in the anogenital region that may cause itching, pain, or bleeding. Condylomata Acuminata (Genital Warts)²⁺ reabsorption 
• Within the cell, Ca CA Condylomata acuminata are a clinical manifestation of genital HPV infection. Condylomata acuminata are described as raised, pearly, flesh-colored, papular, cauliflower-like lesions seen in the anogenital region that may cause itching, pain, or bleeding. Condylomata Acuminata (Genital Warts)²⁺ is bound to the protein calbindin Calbindin Calcium-binding proteins that are found in distal kidney tubules, intestines, brain, and other tissues where they bind, buffer and transport cytoplasmic calcium. Calbindins possess a variable number of ef-hand motifs which contain calcium-binding sites. Some isoforms are regulated by vitamin d. Calcium Hemostasis and Bone Metabolism:
  • Necessary due to the cytotoxic Cytotoxic Parvovirus B19 effects of high intracellular Ca CA Condylomata acuminata are a clinical manifestation of genital HPV infection. Condylomata acuminata are described as raised, pearly, flesh-colored, papular, cauliflower-like lesions seen in the anogenital region that may cause itching, pain, or bleeding. Condylomata Acuminata (Genital Warts)²⁺
  • Transports Ca CA Condylomata acuminata are a clinical manifestation of genital HPV infection. Condylomata acuminata are described as raised, pearly, flesh-colored, papular, cauliflower-like lesions seen in the anogenital region that may cause itching, pain, or bleeding. Condylomata Acuminata (Genital Warts)²⁺ to the basolateral membrane
• Ca CA Condylomata acuminata are a clinical manifestation of genital HPV infection. Condylomata acuminata are described as raised, pearly, flesh-colored, papular, cauliflower-like lesions seen in the anogenital region that may cause itching, pain, or bleeding. Condylomata Acuminata (Genital Warts)²⁺ is moved into the basolateral interstitium via 2 mechanisms:
  • Ca CA Condylomata acuminata are a clinical manifestation of genital HPV infection. Condylomata acuminata are described as raised, pearly, flesh-colored, papular, cauliflower-like lesions seen in the anogenital region that may cause itching, pain, or bleeding. Condylomata Acuminata (Genital Warts)²⁺ ATPase
  • Ca CA Condylomata acuminata are a clinical manifestation of genital HPV infection. Condylomata acuminata are described as raised, pearly, flesh-colored, papular, cauliflower-like lesions seen in the anogenital region that may cause itching, pain, or bleeding. Condylomata Acuminata (Genital Warts)²⁺-Na⁺ exchanger

Magnesium Magnesium A metallic element that has the atomic symbol mg, atomic number 12, and atomic weight 24. 31. It is important for the activity of many enzymes, especially those involved in oxidative phosphorylation. Electrolytes reabsorption

• Reabsorbed via TRPM6 channels Channels The Cell: Cell Membrane
• Does not require a cytosol Cytosol A cell’s cytoskeleton is a network of intracellular protein fibers that provides structural support, anchors organelles, and aids intra- and extracellular movement. The Cell: Cytosol and Cytoskeleton transport protein (such as calbindin Calbindin Calcium-binding proteins that are found in distal kidney tubules, intestines, brain, and other tissues where they bind, buffer and transport cytoplasmic calcium. Calbindins possess a variable number of ef-hand motifs which contain calcium-binding sites. Some isoforms are regulated by vitamin d. Calcium Hemostasis and Bone Metabolism)
• Mechanism for movement into basolateral interstitium is unknown.

Sodium Sodium A member of the alkali group of metals. It has the atomic symbol na, atomic number 11, and atomic weight 23. Hyponatremia reabsorption

Occurs via 2 mechanisms:

• NaCl cotransporter:
  • Na⁺ and Cl^– are reabsorbed.
  • Site of action of thiazide Thiazide Heterocyclic compounds with sulfur and nitrogen in the ring. This term commonly refers to the benzothiadiazines that inhibit sodium-potassium-chloride symporters and are used as diuretics. Hyponatremia diuretics Diuretics Agents that promote the excretion of urine through their effects on kidney function. Heart Failure and Angina Medication
• Epithelial sodium Sodium A member of the alkali group of metals. It has the atomic symbol na, atomic number 11, and atomic weight 23. Hyponatremia channels Channels The Cell: Cell Membrane ( ENaC ENaC Sodium channels found on salt-reabsorbing epithelial cells that line the distal nephron; the distal colon; salivary ducts; sweat glands; and the lung. They are amiloride-sensitive and play a critical role in the control of sodium balance, blood volume, and blood pressure. Liddle Syndrome):
  • Na⁺ is reabsorbed by itself.
  • Creates a voltage gradient because there is no matched transport of other charged ions (i.e., it is not exchanged for another cation, or cotransported with an anion)
  • Also found in the collecting ducts
  • Site of action of amiloride Amiloride A pyrazine compound inhibiting sodium reabsorption through sodium channels in renal epithelial cells. This inhibition creates a negative potential in the luminal membranes of principal cells, located in the distal convoluted tubule and collecting duct. Negative potential reduces secretion of potassium and hydrogen ions. Amiloride is used in conjunction with diuretics to spare potassium loss. Liddle Syndrome (K⁺-sparing diuretic)

Chloride Chloride Inorganic compounds derived from hydrochloric acid that contain the Cl- ion. Electrolytes reabsorption

• Early DCT: paired with Na⁺ via the NaCl cotransporter
• Late DCT (2 mechanisms):
  • Paracellular Paracellular Renal Potassium Regulation:
    • Driven by the electrical gradient Electrical gradient Renal Potassium Regulation generated by ENaC ENaC Sodium channels found on salt-reabsorbing epithelial cells that line the distal nephron; the distal colon; salivary ducts; sweat glands; and the lung. They are amiloride-sensitive and play a critical role in the control of sodium balance, blood volume, and blood pressure. Liddle Syndrome activity
    • Cl^– moves out of the electronegative lumen and toward the electropositive basolateral side.
    • Accounts for the majority of Cl^– transport in the late DCT
  • Transcellular:
    • Apical Cl^– channel → basolateral Cl^–-HCO₃^– exchanger
    • Occurs only at intercalated cells (not abundant in the DCT; primarily located in the collecting ducts)

Potassium Potassium An element in the alkali group of metals with an atomic symbol k, atomic number 19, and atomic weight 39. 10. It is the chief cation in the intracellular fluid of muscle and other cells. Potassium ion is a strong electrolyte that plays a significant role in the regulation of fluid volume and maintenance of the water-electrolyte balance. Hyperkalemia secretion Secretion Coagulation Studies

• K⁺ is not reabsorbed in the DCT, but it is secreted in the late DCT.
• Secretion Secretion Coagulation Studies occurs via ROMK channels Channels The Cell: Cell Membrane of principal cells (primarily located in the collecting ducts, but also present in the late DCT):
  • Driven by electronegative lumen from ENaC ENaC Sodium channels found on salt-reabsorbing epithelial cells that line the distal nephron; the distal colon; salivary ducts; sweat glands; and the lung. They are amiloride-sensitive and play a critical role in the control of sodium balance, blood volume, and blood pressure. Liddle Syndrome (same as in Cl^– reabsorption) 
  • ROMK channels Channels The Cell: Cell Membrane are upregulated by aldosterone Aldosterone A hormone secreted by the adrenal cortex that regulates electrolyte and water balance by increasing the renal retention of sodium and the excretion of potassium. Hyperkalemia.
  • K⁺ secretion Secretion Coagulation Studies through ROMK will increase if ENaC ENaC Sodium channels found on salt-reabsorbing epithelial cells that line the distal nephron; the distal colon; salivary ducts; sweat glands; and the lung. They are amiloride-sensitive and play a critical role in the control of sodium balance, blood volume, and blood pressure. Liddle Syndrome activity increases.

Collecting Ducts

Collecting ducts are the points where multiple nephrons come together during the final stages of urine formation. Intercalated cells and principal cells act to adjust the final composition and concentration of the urine, prior to elimination Elimination The initial damage and destruction of tumor cells by innate and adaptive immunity. Completion of the phase means no cancer growth. Cancer Immunotherapy.

Intercalated cells

Intercalated cells are further divided into α and β subtypes, with each having a slightly different composition of transporters and other proteins Proteins Linear polypeptides that are synthesized on ribosomes and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of amino acids determines the shape the polypeptide will take, during protein folding, and the function of the protein. Energy Homeostasis. 

Apical proteins Proteins Linear polypeptides that are synthesized on ribosomes and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of amino acids determines the shape the polypeptide will take, during protein folding, and the function of the protein. Energy Homeostasis:

• H⁺/K⁺-ATPase:
  • 1 H⁺ out of the cell, 1 K⁺ into the cell
  • Involved in fine-tuning of K⁺ reabsorption
• H⁺-ATPase:
  • 1 H⁺ out of the cell
  • Involved in acid secretion Secretion Coagulation Studies
• Cl^–/HCO₃^– exchanger (β-intercalated cells)
• Cl^– channels Channels The Cell: Cell Membrane

Basolateral proteins Proteins Linear polypeptides that are synthesized on ribosomes and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of amino acids determines the shape the polypeptide will take, during protein folding, and the function of the protein. Energy Homeostasis: 

• Na⁺/K⁺-ATPase
• H⁺-ATPase (β-intercalated cells):
  • Paired with the apical Cl^–/HCO₃^– exchanger
  • Involved with acid homeostasis Homeostasis The processes whereby the internal environment of an organism tends to remain balanced and stable. Cell Injury and Death
• Cl^–/HCO₃^– exchanger (α-intercalated cells):
  • Paired with the apical Cl^– channel
  • Involved with Cl^– reabsorption

Principal cells

Principal cells are responsible for the fine-tuning of Na⁺ and K⁺ in the urine, which is often in response to the hormone aldosterone Aldosterone A hormone secreted by the adrenal cortex that regulates electrolyte and water balance by increasing the renal retention of sodium and the excretion of potassium. Hyperkalemia. Principal cells are also the site of the apical aquaporin channel AQP2, which is a key component in adjusting urine concentration.

Apical proteins Proteins Linear polypeptides that are synthesized on ribosomes and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of amino acids determines the shape the polypeptide will take, during protein folding, and the function of the protein. Energy Homeostasis:

• ENaC ENaC Sodium channels found on salt-reabsorbing epithelial cells that line the distal nephron; the distal colon; salivary ducts; sweat glands; and the lung. They are amiloride-sensitive and play a critical role in the control of sodium balance, blood volume, and blood pressure. Liddle Syndrome channel: 1 Na⁺ moves into cell
  • Na⁺ reabsorption is powered by the Na⁺ gradient generated by Na⁺/K⁺-ATPase.
  • For each Na⁺ that moves into the cell, 1 Cl^– is left behind in the tubular lumen.
  • Creates an electrical gradient Electrical gradient Renal Potassium Regulation where the luminal side is more negative
  • Regulation:
    • ↑ Expression/open probability Probability Probability is a mathematical tool used to study randomness and provide predictions about the likelihood of something happening. There are several basic rules of probability that can be used to help determine the probability of multiple events happening together, separately, or sequentially. Basics of Probability with aldosterone Aldosterone A hormone secreted by the adrenal cortex that regulates electrolyte and water balance by increasing the renal retention of sodium and the excretion of potassium. Hyperkalemia
    • ↑ Distal Na⁺ delivery results in ↑ ENaC ENaC Sodium channels found on salt-reabsorbing epithelial cells that line the distal nephron; the distal colon; salivary ducts; sweat glands; and the lung. They are amiloride-sensitive and play a critical role in the control of sodium balance, blood volume, and blood pressure. Liddle Syndrome channel activity
• ROMK channel ROMK channel Renal Potassium Regulation: 1 K⁺ moves out of cell
  • K⁺ secretion Secretion Coagulation Studies is powered by K⁺ chemical and electrical gradients generated by the Na⁺/K⁺-ATPase and ENaC ENaC Sodium channels found on salt-reabsorbing epithelial cells that line the distal nephron; the distal colon; salivary ducts; sweat glands; and the lung. They are amiloride-sensitive and play a critical role in the control of sodium balance, blood volume, and blood pressure. Liddle Syndrome channels Channels The Cell: Cell Membrane.
  • ROMK channels Channels The Cell: Cell Membrane can open and close; there is an ↑ open probability Probability Probability is a mathematical tool used to study randomness and provide predictions about the likelihood of something happening. There are several basic rules of probability that can be used to help determine the probability of multiple events happening together, separately, or sequentially. Basics of Probability with:
    • Aldosterone Aldosterone A hormone secreted by the adrenal cortex that regulates electrolyte and water balance by increasing the renal retention of sodium and the excretion of potassium. Hyperkalemia
    • ↓ Intracellular ATP (indicates ATP has just been used up by Na⁺/K⁺-ATPase to bring K⁺ into the cell) 
• Aquaporin 2 (AQP2)channel: passive water channel
  • Water in the renal medulla is hypertonic Hypertonic Solutions that have a greater osmotic pressure than a reference solution such as blood, plasma, or interstitial fluid. Renal Sodium and Water Regulation compared to urine due to the countercurrent multiplier system and diluting segments.
  • Water will leave the collecting ducts following its osmotic gradient to allow efflux if aquaporin channels Channels The Cell: Cell Membrane are present.
  • ADH stimulates the production and insertion of aquaporins:
    • ↑ ADH levels → ↑ aquaporins → ↑ water reabsorption → concentrated urine
    • ↓ ADH levels → ↓ aquaporins → ↓ water reabsorption → dilute urine

Basolateral: Na⁺/K⁺-ATPase

• 3 Na⁺ move out of cell and 2 K⁺ move into the cell.
• Stimulated by aldosterone Aldosterone A hormone secreted by the adrenal cortex that regulates electrolyte and water balance by increasing the renal retention of sodium and the excretion of potassium. Hyperkalemia

Summary Table

The following table summarizes the reabsorption, secretion Secretion Coagulation Studies, and important regulatory molecules throughout the tubular system. Regulatory molecules are noted in parentheses, and “+” and “-” indicate stimulation and inhibition, respectively.

Clinical Relevance

• Renal cell carcinoma Renal cell carcinoma Renal cell carcinoma (RCC) is a tumor that arises from the lining of the renal tubular system within the renal cortex. Renal cell carcinoma is responsible for 80%-85% of all primary renal neoplasms. Most RCCs arise sporadically, but smoking, hypertension, and obesity are linked to its development. Renal Cell Carcinoma: the most common primary renal malignancy Malignancy Hemothorax that originates from renal tubular cells (most commonly in the PT).
• SGLT2 inhibitors SGLT2 inhibitors Non-insulinotropic Diabetes Drugs: a class of oral medications used in the management of type 2 Type 2 Spinal Muscular Atrophy diabetes Diabetes Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance. Diabetes Mellitus mellitus. SGLT2 inhibitors SGLT2 inhibitors Non-insulinotropic Diabetes Drugs block glucose Glucose A primary source of energy for living organisms. It is naturally occurring and is found in fruits and other parts of plants in its free state. It is used therapeutically in fluid and nutrient replacement. Lactose Intolerance reabsorption via the SGLT2 transporter in the PT, causing glucose Glucose A primary source of energy for living organisms. It is naturally occurring and is found in fruits and other parts of plants in its free state. It is used therapeutically in fluid and nutrient replacement. Lactose Intolerance to be excreted in the urine rather than being reabsorbed. The names of SGLT2 inhibitors SGLT2 inhibitors Non-insulinotropic Diabetes Drugs end in -gliflozin (e.g., empagliflozin Empagliflozin Non-insulinotropic Diabetes Drugs) and are considered 2nd-line options. An important side effect is the increased risk for genitourinary tract infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease.
• Loop diuretics Diuretics Agents that promote the excretion of urine through their effects on kidney function. Heart Failure and Angina Medication: a commonly used class of diuretics Diuretics Agents that promote the excretion of urine through their effects on kidney function. Heart Failure and Angina Medication (including furosemide Furosemide A benzoic-sulfonamide-furan. It is a diuretic with fast onset and short duration that is used for edema and chronic renal insufficiency. Loop Diuretics, bumetanide Bumetanide A sulfamyl diuretic. Loop Diuretics, and torsemide Torsemide A pyridine and sulfonamide derivative that acts as a sodium-potassium chloride symporter inhibitor. It is used for the treatment of edema associated with congestive heart failure; chronic renal insufficiency; and liver diseases. It is also used for the management of hypertension. Loop Diuretics) that exert their effects by blocking the NKCC2 NKCC2 Renal Potassium Regulation cotransporter in the thick ascending limb Thick ascending limb Renal Sodium and Water Regulation of the loop of Henle. Sodium Sodium A member of the alkali group of metals. It has the atomic symbol na, atomic number 11, and atomic weight 23. Hyponatremia ions remain in the tubule lumen and obligate water to remain with it, resulting in diuretic action. Hypokalemia Hypokalemia Hypokalemia is defined as plasma potassium (K+) concentration < 3.5 mEq/L. Homeostatic mechanisms maintain plasma concentration between 3.5-5.2 mEq/L despite marked variation in dietary intake. Hypokalemia can be due to renal losses, GI losses, transcellular shifts, or poor dietary intake. Hypokalemia is a common side effect due to the action of increased distal delivery of Na⁺ on the ROMK channels Channels The Cell: Cell Membrane. 
• ACEi ACEi A class of drugs whose main indications are the treatment of hypertension and heart failure. They exert their hemodynamic effect mainly by inhibiting the renin-angiotensin system. They also modulate sympathetic nervous system activity and increase prostaglandin synthesis. They cause mainly vasodilation and mild natriuresis without affecting heart rate and contractility. Renin-Angiotensin-Aldosterone System Inhibitors: a commonly used class of antihypertensive drugs that inhibit the RAAS RAAS A blood pressure regulating system of interacting components that include renin; angiotensinogen; angiotensin converting enzyme; angiotensin i; angiotensin ii; and angiotensinase. Renin, an enzyme produced in the kidney, acts on angiotensinogen, an alpha-2 globulin produced by the liver, forming angiotensin I. Angiotensin-converting enzyme, contained in the lung, acts on angiotensin I in the plasma converting it to angiotensin II, an extremely powerful vasoconstrictor. Angiotensin II causes contraction of the arteriolar and renal vascular smooth muscle, leading to retention of salt and water in the kidney and increased arterial blood pressure. In addition, angiotensin II stimulates the release of aldosterone from the adrenal cortex, which in turn also increases salt and water retention in the kidney. Angiotensin-converting enzyme also breaks down bradykinin, a powerful vasodilator and component of the kallikrein-kinin system. Adrenal Hormones at the ACE level. The names of the drugs in this class end in -pril (e.g., lisinopril Lisinopril One of the angiotensin-converting enzyme inhibitors (ACE inhibitors), orally active, that has been used in the treatment of hypertension and congestive heart failure. Renin-Angiotensin-Aldosterone System Inhibitors, enalapril Enalapril An angiotensin-converting enzyme inhibitor that is used to treat hypertension and heart failure. Hypertension Drugs) and are commonly used for the treatment of heart failure Heart Failure A heterogeneous condition in which the heart is unable to pump out sufficient blood to meet the metabolic need of the body. Heart failure can be caused by structural defects, functional abnormalities (ventricular dysfunction), or a sudden overload beyond its capacity. Chronic heart failure is more common than acute heart failure which results from sudden insult to cardiac function, such as myocardial infarction. Total Anomalous Pulmonary Venous Return (TAPVR) and proteinuria Proteinuria The presence of proteins in the urine, an indicator of kidney diseases. Nephrotic Syndrome in Children, in addition to hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension. These drugs are clinically interchangeable with aldosterone Aldosterone A hormone secreted by the adrenal cortex that regulates electrolyte and water balance by increasing the renal retention of sodium and the excretion of potassium. Hyperkalemia receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors blockers.
• Angiotensin II Angiotensin II An octapeptide that is a potent but labile vasoconstrictor. It is produced from angiotensin I after the removal of two amino acids at the c-terminal by angiotensin converting enzyme. The amino acid in position 5 varies in different species. To block vasoconstriction and hypertension effect of angiotensin II, patients are often treated with ace inhibitors or with angiotensin II type 1 receptor blockers. Renal Sodium and Water Regulation receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors blockers: a commonly used class of antihypertensive drugs that inhibit the RAAS RAAS A blood pressure regulating system of interacting components that include renin; angiotensinogen; angiotensin converting enzyme; angiotensin i; angiotensin ii; and angiotensinase. Renin, an enzyme produced in the kidney, acts on angiotensinogen, an alpha-2 globulin produced by the liver, forming angiotensin I. Angiotensin-converting enzyme, contained in the lung, acts on angiotensin I in the plasma converting it to angiotensin II, an extremely powerful vasoconstrictor. Angiotensin II causes contraction of the arteriolar and renal vascular smooth muscle, leading to retention of salt and water in the kidney and increased arterial blood pressure. In addition, angiotensin II stimulates the release of aldosterone from the adrenal cortex, which in turn also increases salt and water retention in the kidney. Angiotensin-converting enzyme also breaks down bradykinin, a powerful vasodilator and component of the kallikrein-kinin system. Adrenal Hormones at the receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors level. The names of the drugs in this class end in -artan (e.g., losartan Losartan An antagonist of angiotensin type 1 receptor with antihypertensive activity due to the reduced pressor effect of angiotensin II. Hypertension Drugs, candesartan) and are commonly used for the treatment of heart failure Heart Failure A heterogeneous condition in which the heart is unable to pump out sufficient blood to meet the metabolic need of the body. Heart failure can be caused by structural defects, functional abnormalities (ventricular dysfunction), or a sudden overload beyond its capacity. Chronic heart failure is more common than acute heart failure which results from sudden insult to cardiac function, such as myocardial infarction. Total Anomalous Pulmonary Venous Return (TAPVR) and proteinuria Proteinuria The presence of proteins in the urine, an indicator of kidney diseases. Nephrotic Syndrome in Children, in addition to hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension. These drugs are clinically interchangeable with ACE inhibitors ACE inhibitors Truncus Arteriosus and are often used when ACE inhibitors ACE inhibitors Truncus Arteriosus are not tolerated owing to the relatively common side effect of coughing (which is not a feature of angiotensin II Angiotensin II An octapeptide that is a potent but labile vasoconstrictor. It is produced from angiotensin I after the removal of two amino acids at the c-terminal by angiotensin converting enzyme. The amino acid in position 5 varies in different species. To block vasoconstriction and hypertension effect of angiotensin II, patients are often treated with ace inhibitors or with angiotensin II type 1 receptor blockers. Renal Sodium and Water Regulation receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors blockers). 
• Diabetes Diabetes Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia and dysfunction of the regulation of glucose metabolism by insulin. Type 1 DM is diagnosed mostly in children and young adults as the result of autoimmune destruction of β cells in the pancreas and the resulting lack of insulin. Type 2 DM has a significant association with obesity and is characterized by insulin resistance. Diabetes Mellitus insipidus ( DI DI Diabetes insipidus (DI) is a condition in which the kidneys are unable to concentrate urine. There are 2 subforms of di: central di (CDI) and nephrogenic di (NDI). Both conditions result in the kidneys being unable to concentrate urine, leading to polyuria, nocturia, and polydipsia. Diabetes Insipidus): a disease resulting from either the lack of ADH secretion Secretion Coagulation Studies (central DI DI Diabetes insipidus (DI) is a condition in which the kidneys are unable to concentrate urine. There are 2 subforms of di: central di (CDI) and nephrogenic di (NDI). Both conditions result in the kidneys being unable to concentrate urine, leading to polyuria, nocturia, and polydipsia. Diabetes Insipidus) or the resistance Resistance Physiologically, the opposition to flow of air caused by the forces of friction. As a part of pulmonary function testing, it is the ratio of driving pressure to the rate of air flow. Ventilation: Mechanics of Breathing to ADH (nephrogenic DI DI Diabetes insipidus (DI) is a condition in which the kidneys are unable to concentrate urine. There are 2 subforms of di: central di (CDI) and nephrogenic di (NDI). Both conditions result in the kidneys being unable to concentrate urine, leading to polyuria, nocturia, and polydipsia. Diabetes Insipidus). The lack of ADH stimulation in the tubular cells results in decreased aquaporin channels Channels The Cell: Cell Membrane in the collecting ducts, which, in turn, leads to decreased water reabsorption, inappropriately dilute urine, and polyuria Polyuria Urination of a large volume of urine with an increase in urinary frequency, commonly seen in diabetes. Renal Potassium Regulation. Treatment includes the administration of desmopressin Desmopressin Hemophilia ( ddAVP DDAVP Hemophilia), an ADH analog.
• V2 receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors blockers: also known as “vaptans,” this class of drugs inhibits the action of ADH at the receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors level. V2 receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors blockers are used in the treatment of SIADH SIADH Syndrome of inappropriate antidiuretic hormone secretion (SIADH) is a disorder of impaired water excretion due to the inability to suppress the secretion of antidiuretic hormone (ADH). SIADH is characterized by impaired water excretion leading to dilutional hyponatremia, which is mainly asymptomatic but may cause neurologic symptoms. S Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH), which causes hyponatremia Hyponatremia Hyponatremia is defined as a decreased serum sodium (sNa+) concentration less than 135 mmol/L. Serum sodium is the greatest contributor to plasma osmolality, which is very tightly controlled via antidiuretic hormone (ADH) release from the hypothalamus and by the thirst mechanism. Hyponatremia from inappropriately high water reabsorption from the aquaporin channels Channels The Cell: Cell Membrane in the collecting duct Collecting duct Straight tubes commencing in the radiate part of the kidney cortex where they receive the curved ends of the distal convoluted tubules. In the medulla the collecting tubules of each pyramid converge to join a central tube (duct of bellini) which opens on the summit of the papilla. Renal Cell Carcinoma. Tolvaptan Tolvaptan A benzazepine derivative and selective vasopressin v2 receptor antagonist that is used to treat euvolemic and hypervolemic hyponatremia. It is also used in the treatment of rapidly progressing autosomal dominant polycystic kidney disease to slow the rate of cyst development and renal insufficiency. Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH) is the most commonly used oral drug in this class.