Overview Proximal Convoluted Tubule The major function of the proximal convoluted tubule (PCT) is isosmotic reabsorption of solutes and water which is imperative for maintaining the extracellular fluid (ECF) this is accomplished by a number of co-transporters such as Na+-glucose co-transporter (SGLT) 100% of the filtered glucose is reabsorbed Na+-amino acid co-transporter 100% of the filtered amino acids are reabsorbed Na+-phosphate co-transporter Na+-H+ exchange Note that the PCT can be divided into an early and late PCT Na+ is reabsorbed in both portions of the PCT but via different mechanisms early PCT Na+ is primarily reabsorbed with HCO3- 85% of the filtered HCO3- is reabsorbed Na+ is also reabsorbed with glucose, amino acids, and other organic solutes (e.g., lactate and citrate) late PCT Na+ is primarily reabsorbed with Cl- There are a number of hormones that act on the PCT and they include parathyroid hormone (PTH) inhibits the Na+-phosphate co-transporter angiotensin II stimultes the Na+-H+ exchange Medications that act on this portion of the nephrone includes carbonic anhydrase inhibitors (e.g., acetazolamide) osmotic diuretics (e.g., mannitol) Thin Descending Loop of Henle The thin descending loop of Henle is permeable to water but not ions water moves out of the loop into the interstitium resulting in the tubular fluid becoming more concentrated (hyperosmotic) Thick Ascending Loop of Henle The major function of the thick ascending loop of Henle is to reabsorb NaCl without water this is accomplished by the Na+-K+-2Cl− cotransporter loop diuretics (e.g., furosemide) act on these transporters reabsorption of solutes without water makes the tubular fluid dilute (thus why this is the diluting segment) There is also paracellular reabsorption of Ca2+ and Mg2+ this is driven by the lumen-positive potential difference generated by K+ backleak Distal Convoluted Tubule and Collecting Duct The distal convoluted tubule (DCT) can be divided into an early and late DCT early DCT reabsorbs 5% of the filtered sodium via a Na+-Cl− cotransporter this is the site of action of thiazide (e.g., hydrochlorothiazide and metolazone) diuretics thiazides are organic acids that bind to the Cl− site of the transporter it is impermeable to water and thus dilutes the tubular fluid (thus called the cortical diluting segment) late DCT and collecting duct both of these segments of the nephron are anatomically and functionally similar there are 2 major cell types principal cells Na+ is reabsorbed via epithelial Na+ channels (ENaC) aldosterone increases Na reabsorption via increased protein synthesis of ENaC and Na+-K+-ATPase aldosterone also stimulates K+ secretion via acting on K+ channels K+-sparing diuretics (e.g., spironolactone, amiloride, and triamterene) impair Na+ reabsorption spironolactone is an aldosterone antagonist amiloride and triamterene act at the level of Na+ channels anti-diuretic hormone (ADH) increases water permeability of the principal cells this is accomplished by binding to V2 receptors and subsequently resulting in increased aquaporin-2 (AQP2) channel expression there is a Ca2+-Na+ exchange in the basolateral membrane of the principle cell PTH increases Ca2+ reabsorption by increase exchange activity α-intercalated cells secretion of H+ is accomplished by 2 active transport mechanisms H+-ATPase this enzyme is stimulated by aldosterone H+-K+ ATPase H+ is secreted in exchange for K+