Sodium handling along the nephron

Proximal Tubule - The Workhorse

• Primary Site of Na⁺ Reabsorption: Reclaims ~65-80% of filtered Na⁺.
• Mechanism: Iso-osmotic reabsorption.
  • Basolateral: Na⁺/K⁺ ATPase pump actively transports Na⁺ into the interstitium, creating a low intracellular Na⁺ concentration.
  • Apical: Na⁺ enters the cell down its gradient via various cotransporters and exchangers.
    • NHE3: Na⁺/H⁺ exchanger (major driver).
    • SGLT2: Na⁺/glucose cotransporter.
    • Na⁺/amino acid & Na⁺/phosphate cotransporters.
• Water Follows Sodium: Water is passively reabsorbed, following the osmotic gradient created by solute movement.

⭐ Angiotensin II stimulates Na⁺ reabsorption in the PT by upregulating the Na⁺/H⁺ exchanger (NHE3).

Loop of Henle - The Dilutor

• Primary Function: Creates a hypertonic medullary interstitium & dilutes tubular fluid.
• Descending Limb:
  • Highly permeable to H₂O, impermeable to NaCl.
  • Passive H₂O reabsorption → concentrates filtrate (↑ osmolarity).
• Ascending Limb:
  • Impermeable to H₂O.
  • Thick Ascending Limb (TAL): Actively reabsorbs ~25% of filtered Na⁺, K⁺, and Cl⁻ via the Na⁺-K⁺-2Cl⁻ (NKCC2) cotransporter.
    • Generates a lumen-positive potential, driving paracellular reabsorption of Mg²⁺ and Ca²⁺.

⭐ The Thick Ascending Limb is the primary target for loop diuretics (e.g., Furosemide), which potently inhibit the NKCC2 cotransporter, leading to significant natriuresis and diuresis.

Distal Convoluted Tubule - The Fine-Tuner

• Reabsorbs 5-10% of filtered $Na^+$.
• Apical Transporter: Na-Cl Cotransporter (NCC).
  • Target of Thiazide diuretics (e.g., Hydrochlorothiazide).
• Basolateral Pump: $Na^+/K^+$ ATPase maintains the sodium gradient.
• Hormonal Control:
  • Parathyroid Hormone (PTH): ↑ $Ca^{2+}$ reabsorption via an apical channel and basolateral $Na^+/Ca^{2+}$ exchanger.
  • Aldosterone: Acts on principal cells (late DCT/collecting duct) to ↑ $Na^+$ reabsorption.
• Relatively impermeable to water.

⭐ Thiazide diuretics block the NCC, causing natriuresis. The resulting lower intracellular $Na^+$ enhances the basolateral $Na^+/Ca^{2+}$ exchanger activity, leading to increased calcium reabsorption (hypocalciuria).

Collecting Duct - The Final Arbiter

• Principal Cells: Regulate final Na+ excretion, reabsorbing ~2-3% of filtered load via the Epithelial Na+ Channel (ENaC).

  • Aldosterone: Upregulates ENaC and Na+/K+ pump activity → ↑ Na+ reabsorption, ↑ K+ secretion.
  • ADH: Primarily acts on water reabsorption (aquaporins), but concentrating the lumen can slightly enhance the gradient for Na+ uptake.

• K+-Sparing Diuretics: Target this segment.

  • Amiloride, Triamterene: Block ENaC.
  • Spironolactone, Eplerenone: Aldosterone antagonists.

⭐ Liddle Syndrome: A gain-of-function ENaC mutation mimics hyperaldosteronism (hypertension, hypokalemia) but with low aldosterone & renin.

High‑Yield Points - ⚡ Biggest Takeaways

• The proximal tubule reabsorbs the vast majority of filtered sodium (~65-80%), driven by the basolateral Na+/K+-ATPase.
• The thick ascending limb reabsorbs ~15-25% via the Na-K-2Cl cotransporter, the primary target for loop diuretics.
• The distal tubule reabsorbs ~5% via the Na-Cl cotransporter, the site of action for thiazide diuretics.
• The collecting duct fine-tunes reabsorption (1-3%) through the ENaC channel, which is upregulated by aldosterone.
• Angiotensin II stimulates Na+ reabsorption, primarily in the proximal tubule.