| First Author | Abdel Khalek W | Year | 2019 |
| Journal | J Am Soc Nephrol | Volume | 30 |
| Issue | 5 | Pages | 811-823 |
| PubMed ID | 30967423 | Mgi Jnum | J:283218 |
| Mgi Id | MGI:6378990 | Doi | 10.1681/ASN.2017121307 |
| Citation | Abdel Khalek W, et al. (2019) Severe Arterial Hypertension from Cullin 3 Mutations Is Caused by Both Renal and Vascular Effects. J Am Soc Nephrol 30(5):811-823 |
| abstractText | BACKGROUND: 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 result in familial hyperkalemic hypertension (FHHt), a rare Mendelian form of human arterial hypertension. Although all mutations result in an increased abundance of WNK1 or WNK4, all FHHt-causing CUL3 mutations, resulting in the skipping of exon 9, lead to a more severe phenotype. METHODS: We created and compared two mouse models, one expressing the mutant Cul3 protein ubiquitously (pgk-Cul39) and the other specifically in vascular smooth muscle cells (SM22-Cul39). We conducted pharmacologic investigations on isolated aortas and generated stable and inducible HEK293 cell lines that overexpress the wild-type Cul3 or mutant Cul3 (Cul39) protein. RESULTS: As expected, pgk-Cul39 mice showed marked hypertension with significant hyperkalemia, hyperchloremia and low renin. BP increased significantly in SM22-Cul39 mice, independent of any measurable effect on renal transport. Only pgk-Cul39 mice displayed increased expression of the sodium chloride cotransporter and phosphorylation by the WNK-SPAK kinases. Both models showed altered reactivity of isolated aortas to phenylephrine and acetylcholine, as well as marked acute BP sensitivity to the calcium channel blocker amlodipine. Aortas from SM22-Cul39 mice showed increased expression of RhoA, a key molecule involved in regulation of vascular tone, compared with aortas from control mice. We also observed increased RhoA abundance and t 1/2 in Cul39-expressing cells, caused by decreased ubiquitination. CONCLUSIONS: Mutations in Cul3 cause severe hypertension by affecting both renal and vascular function, the latter being associated with activation of RhoA. |
