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

Abstract

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.

An exploratory analysis of the competing effects of aggressive decongestion and high-dose loop diuretic therapy in the DOSE trial

“…However, this cotransporter also functions to deliver chloride to the cells of the macula densa, allowing the kidney to sense tubular delivery of sodium chloride. 38 When this channel is blocked, the kidney perceives reduced salt delivery, and increases renin secretion and sympathetic nervous system activity accordingly. 38 These effects have been demonstrated to have clinically measurable effects on hemodynamics in humans with decompensated heart failure, resulting in a decrease in stroke volume, increase in wedge pressure, and increase in systemic vascular resistance, all of which occur prior to meaningful natriuresis.…”

Genetics of Magnesium Disorders

“…ROMK, ClC-Kb, and barttin cross the boundary of TAL and are expressed in the distal convoluted tubule (DCT). They have been described in detail in the context of salt-losing nephropathy ( Table 1 ) [24][25][26][27][28][29] .…”

MAGE-D2 and the Regulation of Renal Salt Transporters

“…Gs-alpha may participate in the vasopressin-induced cyclic AMP-signaling cascade and thereby stimulate the activity of NKCC2 and NCC by promoting their insertion into the plasma membrane. 7,8 The transient nature of the salt-wasting phenotype is intriguing but unexplained. Laghmani et al speculate that higher sensitivity of adenylate cyclase activity to vasopressin during development or increasing levels of oxygenation in the kidney during gestation might underlie this transience.…”