Cullin 3 mutant causing familial hyperkalemic hypertension lacks normal activity in the kidney

Abstract

CUL3 mutation (CUL3-Δ9) causes familial hyperkalemic hypertension (FHHt) by reducing adaptor KLHL3, impairing substrate WNK4 degradation. Whether CUL3-Δ9 affects other targets in kidneys remains unclear. We found that CUL3-Δ9 cannot degrade two CUL3 targets, cyclin E and nuclear factor erythroid-2-related factor 2 (NRF2; using a surrogate marker NQO1), or rescue injury or polyuria caused by Cul3 disruption. In an FHHt model, CUL3-Δ9 impaired NRF2 degradation without reduction of its adaptor KEAP1. Our data provide additional insights into CUL3-Δ9 function in the kidney.