Hyperkalemic hypertension–associated cullin 3 promotes WNK signaling by degrading KLHL3

摘要: Familial hyperkalemic hypertension (FHHt) is a monogenic disease resulting from mutations in genes encoding WNK kinases, the ubiquitin scaffold protein cullin 3 (CUL3), or substrate adaptor kelch-like (KLHL3). Disease-associated CUL3 abrogate kinase degradation cells, but it not clear how mutant forms of promote stability. Here, we demonstrated that an FHHt-causing (CUL3 Δ403–459) only retains ability to bind and ubiquitylate kinases KLHL3 also more heavily neddylated activated than WT CUL3. In Δ403–459 depleted KLHL3, preventing degradation, despite increased CUL3-mediated ubiquitylation; therefore, loss kidney should phenocopy FHHt murine models. As predicted, nephron-specific deletion Cul3 mice did increase levels abundance phosphorylated Na-Cl cotransporter (NCC). Over time, however, caused renal dysfunction, including hypochloremic alkalosis, diabetes insipidus, salt-sensitive hypotension, with depletion sodium potassium chloride 2 aquaporin 2. Moreover, these animals exhibited inflammation, fibrosis, cyclin E. These results indicate FHHt-associated targets for thereby whereas general activity — while impairing has widespread toxic effects kidney.