Angiotensin II signaling via protein kinase C phosphorylates Kelch-like 3, preventing WNK4 degradation
Abstract
Aldosterone produces distinct adaptive responses in volume depletion and hyperkalemia. Mutations in with-no-lysine (WNK) kinases or ubiquitin ligases containing Cullin 3 (CUL3) and Kelch-like 3 (KLHL3) cause a Mendelian disease featuring hypertension and hyperkalemia due to constitutive renal salt reabsorption and inhibited K+ secretion. WNKs modulate activities of aldosterone-regulated electrolyte flux pathways, and WNK levels are regulated by CUL3/KLHL3; disease-causing mutations prevent WNK degradation. This manuscript shows that angiotensin II (AII), a hormone produced only in volume depletion, induces PKC-mediated phosphorylation of KLHL3, preventing WNK degradation and phenocopying KLHL3 mutations. These findings provide a mechanism by which AII signaling alters WNK4, promoting increased renal salt reabsorption and reduced K+ secretion.
- Publication:
-
Proceedings of the National Academy of Science
- Pub Date:
- October 2014
- DOI:
- 10.1073/pnas.1418342111
- Bibcode:
- 2014PNAS..11115556S