Khalek WA, et al. - Because mutations in four genes, WNK lysine deficient protein kinase 1 and 4 (WNK1 and WNK4), kelch like family member 3 (KLHL3), or Cullin 3 (CUL3), can lead to familial hyperkalemic hypertension (FHHt), a rare Mendelian form of human arterial hypertension, researchers studied why CUL3 mutations result in a more severe phenotype by creating and comparing two mouse models, one expressing the mutant Cul3 protein ubiquitously (pgk-Cul3∆9) and the other specifically in vascular smooth muscle cells (SM22-Cul3∆9). According to results, pgk-Cul3∆9 mice with significant hyperkalemia, hyperchloremia and low renin showed marked hypertension as expected. Findings suggested that Cul3 mutations cause severe hypertension by affecting both renal and vascular function, the latter related to RhoA activation.