Physiology and pathophysiology of the renal Na-K-2Cl cotransporter (NKCC2)

Am J Physiol Renal Physiol. 2014 Nov 1;307(9):F991-F1002. doi: 10.1152/ajprenal.00432.2014. Epub 2014 Sep 3.


The Na-K-2Cl cotransporter (NKCC2; BSC1) is located in the apical membrane of the epithelial cells of the thick ascending limb of the loop of Henle (TAL). NKCC2 facilitates ∼20-25% of the reuptake of the total filtered NaCl load. NKCC2 is therefore one of the transport proteins with the highest overall reabsorptive capacity in the kidney. Consequently, even subtle changes in NKCC2 transport activity considerably alter the renal reabsorptive capacity for NaCl and eventually lead to perturbations of the salt and water homoeostasis. In addition to facilitating the bulk reabsorption of NaCl in the TAL, NKCC2 transport activity in the macula densa cells of the TAL constitutes the initial step of the tubular-vascular communication within the juxtaglomerular apparatus (JGA); this communications allows the TAL to modulate the preglomerular resistance of the afferent arteriole and the renin secretion from the granular cells of the JGA. This review provides an overview of our current knowledge with respect to the general functions of NKCC2, the modulation of its transport activity by different regulatory mechanisms, and new developments in the pathophysiology of NKCC2-dependent renal NaCl transport.

Keywords: NKCC2; Slc12a1; differential splicing; macula densa; thick ascending limb.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Alternative Splicing
  • Animals
  • Bartter Syndrome / physiopathology
  • Gene Expression Regulation
  • Humans
  • Kidney
  • Loop of Henle / metabolism*
  • Mice
  • Protein Isoforms / physiology
  • Solute Carrier Family 12, Member 1 / genetics
  • Solute Carrier Family 12, Member 1 / physiology*


  • Protein Isoforms
  • Solute Carrier Family 12, Member 1