The sodium chloride cotransporter SLC12A3: new roles in sodium, potassium, and blood pressure regulation

Abstract

SLC12A3 encodes the thiazide-sensitive sodium chloride cotransporter (NCC), which is primarily expressed in the kidney, but also in intestine and bone. In the kidney, NCC is located in the apical plasma membrane of epithelial cells in the distal convoluted tubule. Although NCC reabsorbs only 5 to 10 % of filtered sodium, it is important for the fine-tuning of renal sodium excretion in response to various hormonal and non-hormonal stimuli. Several new roles for NCC in the regulation of sodium, potassium, and blood pressure have been unraveled recently. For example, the recent discoveries that NCC is activated by angiotensin II but inhibited by dietary potassium shed light on how the kidney handles sodium during hypovolemia (high angiotensin II) and hyperkalemia. The additive effect of angiotensin II and aldosterone maximizes sodium reabsorption during hypovolemia, whereas the inhibitory effect of potassium on NCC increases delivery of sodium to the potassium-secreting portion of the nephron. In addition, great steps have been made in unraveling the molecular machinery that controls NCC. This complex network consists of kinases and ubiquitinases, including WNKs, SGK1, SPAK, Nedd4-2, Cullin-3, and Kelch-like 3. The pathophysiological significance of this network is illustrated by the fact that modification of each individual protein in the network changes NCC activity and results in salt-dependent hypotension or hypertension. This review aims to summarize these new insights in an integrated manner while identifying unanswered questions.

A Cation-Chloride Cotransporter Gene Is Required for Cell Elongation and Osmoregulation in Rice

“…In animals, it has been reported that a cation-chloride cotransporter (CCC) family (also called SLC12) is involved in transport of K + , Na + , and Cl 2 (Russell, 2000;Hebert et al, 2004;Gamba, 2005 (Hoffmann et al, 2009;Lindinger et al, 2011;Moes et al, 2014). CCC family genes were also found in the plant genome, but only a few of them have been functionally characterized.…”

Direct and Indirect Mineralocorticoid Effects Determine Distal Salt Transport

“…5,6 Although the canonical action of aldosterone is to increase epithelial Na + channel (ENaC) activity, it is accepted that aldosterone also stimulates the thiazide-sensitive Na + -Cl 2 cotransporter (NCC). 7,8 Aldosterone infusion increases NCC activity 9 and NCC abundance. 10 Dietary salt restriction increases the abundance of phosphorylated (activated) Na + -Cl 2 cotransporter (pNCC).…”

Thiazide-sensitive Na<sup>+</sup>–Cl<sup>−</sup> cotransporter: genetic polymorphisms and human diseases

“…Several members of the electroneutral cotransporter gene family are potentially implicated in hypertension, such as NKCC2 [83], KCC3 [84], TSC [85], epithelial sodium channel [86], and renal epithelial chloride channel [87]. Besides that TSC is the target of thiazide diuretics that are used in treatment of hypertension [9], it was reported that null mutant (TSC −/− ) mice carried a lower blood pressure than wild-type mice during Na + restriction in animal models [88].…”

“…Nedd4-2 is a ubiquitinase which induces ubiquitylation of TSC and decreases its activity and surface expression in vitro and in vivo, while SGK1 could prevent these effects [118]. In addition, Cullin-3 and Kelch-like 3, two ubiquitinases, were also found to regulate TSC via ubiquitinating WNK4 [85]. Protein kinase network regulates TSC activity via phosphorylation and ubiquitylation, and we expect that this complex network system may help to identify patients with hypertension and can be the choice of antihypertensive medication in the future.…”

“…Moreover, some functional variants of SPAK, such as STK39, could alter renal NaCl distribution in essential hypertension through regulation of TSC activity [109,110]. Figure 3 shows the regulation of TSC by multiple kinases and ubiquitinases, such as WNKs, serine-threonine kinase (SGK1), SPAK, Nedd4-2, Cullin-3, and Kelch-like 3 [85,111]. TSC regulation by WNK4 has been complicated by contradictory researches [22,[78][79][80][112][113][114], indicating that WNK4 regulation effects may coexist and be modulated by specific factors, such as renin-angiotensin system [112] and intracellular chloride concentration [115].…”