Familial Hyperkalemic Hypertension (FHHt) is caused by mutations in WNK1, WNK4, KLHL3 or CUL3 (cullin-3). Patients with CUL3 mutation display a more severe phenotype. The mechanisms associated with this severity remain unclear.Design and method:
All CUL3 mutations result in the skipping of exon 9. We have generated a mouse model of “Cul3-FHHt” by deleting Cul3 exon 9.Results:
RT-PCR proved that the exon skipping occurred as expected in the kidney of Cul3+/d9 mice. They developed the classical FHHt features, which were all corrected by hydrochlorothiazide administration, a blocker of the Na+-Cl- cotransporter NCC. Accordingly, NCC expression and phosphorylation were increased in Cul3+/d9 mice. Cul3+/d9 mice are smaller and lighter than control littermates. Preliminary results suggest that this could be due to the hyperkalemia and/or metabolic acidosis. Cul3 serves as a scaffold for RING-type E3 ubiquitin-ligase complexes. It interacts with KLHL3, which recruits the substrates (such as WNK1/4) for ubiquitination. The consequences of exon 9 skipping on Cul3 activity are still debated. It could result in an increased degradation of KLHL3 and thus decreased recruitment and degradation of the substrates. However, the expression level of KLHL3 was similar in Cul3+/d9 and control mice.Conclusions:
As in humans, the phenotype of Cul3-FHHt mice is more severe than that of the WNK1-FHHt mice we previously described. Two hypotheses have been proposed: a broader dysfunction of the distal nephron or an increased vascular reactivity. Further studies of the Cul3+/d9 mice are required to define the causes of this severity.