Abstract
The renal thiazide-sensitive NaCl cotransporter, NCC, is the major pathway for salt reabsorption in the distal convoluted tubule. The activity of this cotransporter is critical for regulation of several physiological variables such as blood pressure, serum potassium, acid base metabolism, and urinary calcium excretion. Therefore, it is not surprising that numerous hormone-signaling pathways regulate NCC activity to maintain homeostasis. In this review, we will provide an overview of the most recent evidence on NCC modulation by aldosterone, angiotensin II, vasopressin, glucocorticoids, insulin, norepinephrine, estradiol, progesterone, prolactin, and parathyroid hormone.
Highlights
IN THE DISTAL CONVOLUTED TUBULE (DCT), Naϩ and ClϪ reabsorption is fine tuned by the electroneutral Naϩ-ClϪ cotransporter (NCC) [13] expressed in the apical membrane and target of the thiazide-type diuretics [11]
Phosphorylation by the kinase STE-20 proline-alanine-rich (SPAK) in the NCC amino-terminal domain [38] [which in turn is modulated by the “with no lysine kinases” (WNKs)] is associated with the activation of the cotransporter [35, 39], and ubiquitylation by either a direct effect of the HECT-type E3 ubiquitin ligase complex, Nedd4-2, which reduces the amount or activity of NCC in the plasma membrane [2, 41], or an indirect effect of the RING-type ubiquitin ligase complex, KLHL3 and Cul3, that modulates the ubiquitylation of WNKs [3, 25]
Some evidence suggests that it could be through modulation of WNK4 activity and/or SGK1 activation [43, 54], and a recent study showed that WNK1 is a target of Nedd4-2, an effect of the ligase that is inhibited by SGK1 [42]
Summary
It was first reported in 2007 that administration of captopril, an ANG II-receptor antagonist, in rats acutely promoted the redistribution of apical NCC to cytoplasmic vesicles and that the coadministration of ANG II reversed this effect [45]. In Xenopus laevis oocytes ANG II promoted NCC activation by a WNK4- and SPAK-dependent mechanism [44]. It was observed that in rats exposed to a LSD, NCC apical expression increased in an aldosterone-independent fashion [12]. Another work showed that chronic ANG II infusion
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