The thick ascending limb of the loop of Henle is impermeable to water despite high osmolarity in the medullary interstitium. Which ion transporter is primarily responsible for active NaCl reabsorption in this segment?

Explanation

## Thick Ascending Limb (TAL) — Ion Transport and Osmotic Gradient **Key Point:** The thick ascending limb actively reabsorbs NaCl via the **Na⁺-K⁺-2Cl⁻ cotransporter (NKCC2)** on the apical membrane, but remains **impermeable to water**, making it the "diluting segment." ### Mechanism of NaCl Reabsorption in TAL 1. **Apical Entry** — NKCC2 cotransporter couples the inward movement of Na⁺, K⁺, and 2 Cl⁻ ions - This is an **electroneutral** transporter (no net charge movement) - Driven by the **Na⁺ gradient** established by basolateral Na⁺-K⁺-ATPase 2. **Basolateral Extrusion** - Na⁺ pumped out via **Na⁺-K⁺-ATPase** (uses ATP) - Cl⁻ exits via **Cl⁻ channels** - K⁺ recycled back to apical membrane via **ROMK channels** (renal outer medullary potassium channels) 3. **Water Impermeability** - TAL **lacks aquaporins** on apical membrane - Despite high osmolarity in medullary interstitium, water cannot follow solutes - This creates the **osmotic gradient** essential for the countercurrent multiplier **High-Yield:** NKCC2 is the **target of loop diuretics** (furosemide, bumetanide, torsemide). Blocking this transporter prevents NaCl reabsorption, leading to massive natriuresis and potent diuresis. This is why loop diuretics are the most potent diuretic class. **Mnemonic:** **"TAL = Thick, Active, Limit water"** — the thick ascending limb actively reabsorbs ions but limits (blocks) water reabsorption. ### Comparison of Loop of Henle Segments | Feature | Descending Limb | Thin Ascending Limb | Thick Ascending Limb | | --- | --- | --- | --- | | **Water Permeability** | High (aquaporin-1) | Low | None (no aquaporins) | | **NaCl Permeability** | Low | High (passive) | High (active via NKCC2) | | **Primary Function** | Water reabsorption | Passive NaCl reabsorption | Active NaCl reabsorption | | **Osmolarity Effect** | Equilibrates with medulla | Dilutes tubular fluid | Creates osmotic gradient | | **Diuretic Sensitivity** | Not affected | Not affected | **Loop diuretic target** | **Clinical Pearl:** Patients on loop diuretics (especially chronic use) develop **hypokalemia** because: - NKCC2 blockade → ↓ K⁺ reabsorption in TAL - Increased distal K⁺ delivery → enhanced K⁺ secretion in collecting duct (aldosterone-stimulated) - Net result: significant urinary K⁺ loss ### Why TAL is the "Diluting Segment" The thick ascending limb removes NaCl (osmotically active solute) without allowing water to follow. This makes the tubular fluid **hypotonic** relative to plasma — hence the term "diluting segment." The reabsorbed NaCl is deposited into the medullary interstitium, raising its osmolarity and enabling water reabsorption in the collecting duct. [cite:Guyton & Hall Textbook of Medical Physiology 13e Ch 26]