NKCC2

NKCC2, encoded by the SLC12A1 gene, is a sodium–potassium–chloride cotransporter located in the thick ascending limb of the loop of Henle in the kidney. It reabsorbs Na+, K+, and Cl− from the luminal fluid into tubular epithelial cells, contributing to the generation of the medullary osmotic gradient and the kidney's ability to concentrate urine.

The transporter operates as an electroneutral symporter with a 1 Na+:1 K+:2 Cl− stoichiometry, driven by the basolateral Na+/K+ ATPase. It is localized mainly on the apical membrane of TAL cells and is also present in macula densa cells, where it participates in tubuloglomerular feedback sensing of luminal NaCl.

Regulation occurs through WNK kinases (WNK1 and WNK4) and the downstream SPAK/OSR1 kinases, which phosphorylate and activate NKCC2 in response to volume depletion and low distal NaCl delivery. Hormonal and paracrine signals, including angiotensin II, can modulate TAL transporter activity, coordinating renal salt handling with systemic volume status.

Pharmacologically, loop diuretics such as furosemide, bumetanide, and torasemide inhibit NKCC2 by binding to the luminal face. They are secreted into the tubular lumen and block Na+, K+, and Cl− reabsorption, producing natriuresis and calciuresis. Adverse effects include hypokalemia, hypomagnesemia, metabolic alkalosis, and, with high doses, ototoxicity.

Pathophysiologically, loss-of-function mutations in SLC12A1 cause Bartter syndrome type I, characterized by salt wasting, hypokalemia, metabolic alkalosis, and growth or developmental issues in infancy. NKCC2 function is essential for proper salt reabsorption in the TAL and for the kidney’s ability to concentrate urine.