Renal Physiology: Aldosterone-Dependent NCC

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RESEARCH HIGHLIGHTS Nature Reviews Nephrology 11, 567 (2015); published online 25 August 2015; doi:10.1038/nrneph.2015.145

RENAL PHYSIOLOGY Aldosterone-dependent NCC activation A new study has identified a mechanism Further investigations in cell culture linking aldosterone to activation of the NaCl models demonstrated that WNK1 acts cotransporter (NCC), which has important downstream of NEDD4-2 and SGK1 to roles in renal sodium reabsorption and modulate NCC activity, suggesting an blood-pressure homeostasis. “Aldosterone is essential role of WNK1 in the aldosterone a potent NCC activator, but the mechanism response. Consistent with these data, by which it interfaces with the WNK kinase aldosterone infusion increased the levels pathway to trigger NCC phosphorylation of proline-rich Wnk1 isoforms in wild and activation had not been defined,” type mice, but not in Nedd4-2 knockout explains researcher Arohan Subramanya. mice, which had high Wnk1 expression When analysing the sequence of WNK1 and NCC activity at baseline. kinase, Subramanya and colleagues “Our data suggest that alterations in noticed binding sites for the ubiquitin WNK-dependent signalling contribute ligase NEDD4-2 in an proline-rich region to the pathogenesis of diseases of that undergoes alternative splicing. They aldosterone excess, and add to the found that WNK1 isoforms containing emerging paradigm that drugs that block these binding sites were highly expressed in WNK kinases could be used to treat a human distal nephrons and were targeted variety of common conditions, such as for proteasomal degradation by NEDD4-2. hypertension and congestive heart failure,” “As NEDD4-2 can be blocked by the concludes Subramanya. aldosterone-induced kinase SGK1, this Ellen F. Carney finding suggested a mechanism by which aldosterone could increase WNK1 levels, Original article Roy, A. et al. Alternatively spliced proline- resulting in increased WNK signalling and rich cassettes link WNK1 to aldosterone action. J. Clin. Invest. doi:10.1172/JCI75245 phosphorylation of NCC,” says Subramanya.