Abstract
The pathogenesis of essential hypertension remains unknown, but thiazide diuretics are frequently recommended as first-line treatment. Recently, familial hyperkalemic hypertension (FHHt) was shown to result from activation of the thiazide-sensitive Na-Cl cotransporter (NCC) by mutations in WNK4, although the mechanism for this effect remains unknown. WNK kinases are unique members of the human kinome, intimately involved in maintaining electrolyte balance across cell membranes and epithelia. Previous work showed that WNK1, WNK4, and a kidney-specific isoform of WNK1 interact to regulate NCC activity, suggesting that WNK kinases form a signaling complex. Here, we report that WNK3, another member of the WNK kinase family expressed by distal tubule cells, interacts with WNK4 and WNK1 to regulate NCC in both human kidney cells and Xenopus oocytes, further supporting the WNK signaling complex hypothesis. We demonstrate that physiological regulation of NCC in oocytes results from antagonism between WNK3 and WNK4 and that FHHt-causing WNK4 mutations exert a dominant-negative effect on wild-type (WT) WNK4 to mimic a state of WNK3 excess. The results provide a mechanistic explanation for the divergent effects of WT and FHHt-mutant WNK4 on NCC activity, and for the dominant nature of FHHt in humans and genetically modified mice.
Highlights
Hypertension affects 50 million Americans, contributing importantly to myocardial infarction, kidney failure, and stroke
WNK1 can inhibit the effects of WNK4 on Na-Cl cotransporter (NCC), and KS-WNK1 can inhibit the effects of WNK1 on WNK4 and, indirectly, NCC. These results suggest that WNK kinases do not act alone, but instead constitute a signaling complex in the aldosteronesensitive distal nephron (ASDN)
WNK3 stimulates NCC activity via its carboxyterminal domain
Summary
Hypertension affects 50 million Americans, contributing importantly to myocardial infarction, kidney failure, and stroke. Treatment of hypertension remains largely empiric, but a consistent feature of the pharmacological approach during the past 50 years has been the central role of thiazide diuretics, drugs frequently recommended as first-line agents [2]. These drugs were developed without an understanding of their mechanism of action, but it is recognized that they are specific antagonists of an Na-Cl cotransporter (thiazide-sensitive Na-Cl cotransporter [NCC]; SLC12A3) that is expressed exclusively along a short segment of mammalian nephron, the distal convoluted tubule (DCT) [3]. These advances include the discovery that one form of monogenic human hypertension, familial hyperkalemic hypertension (FHHt; OMIM 145260; called pseudohypoaldosteronism type II or Gordon syndrome), can be caused by activation of NCC within the DCT [6, 7]
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