The Nephron

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⁺