| First Author | Ferdaus MZ | Year | 2017 |
| Journal | JCI Insight | Volume | 2 |
| Issue | 24 | PubMed ID | 29263298 |
| Mgi Jnum | J:287902 | Mgi Id | MGI:6407553 |
| Doi | 10.1172/jci.insight.96700 | Citation | Ferdaus MZ, et al. (2017) Mutant Cullin 3 causes familial hyperkalemic hypertension via dominant effects. JCI Insight 2(24) |
| abstractText | Mutations in the ubiquitin ligase scaffold protein Cullin 3 (CUL3) cause the disease familial hyperkalemic hypertension (FHHt). In the kidney, mutant CUL3 (CUL3-Delta9) increases abundance of With-No-Lysine [K] Kinase 4 (WNK4), with excessive activation of the downstream Sterile 20 (STE20)/SPS-1-related proline/alanine-rich kinase (SPAK) increasing phosphorylation of the Na+-Cl- cotransporter (NCC). CUL3-Delta9 promotes its own degradation via autoubiquitination, leading to the hypothesis that Cul3 haploinsufficiency causes FHHt. To directly test this, we generated Cul3 heterozygous mice (CUL3-Het), and Cul3 heterozygotes also expressing CUL3-Delta9 (CUL3-Het/Delta9), using an inducible renal epithelial-specific system. Endogenous CUL3 was reduced to 50% in both models, and consistent with autoubiquitination, CUL3-Delta9 protein was undetectable in CUL3-Het/Delta9 kidneys unless primary renal epithelia cells were cultured. Abundances of WNK4 and phosphorylated NCC did not differ between control and CUL3-Het mice, but they were elevated in CUL3-Het/Delta9 mice, which also displayed higher plasma [K+] and blood pressure. Abundance of phosphorylated Na+-K+-2Cl- cotransporter (NKCC2) was also increased, which may contribute to the severity of CUL3-Delta9-mediated FHHt. WNK4 and SPAK localized to puncta in NCC-positive segments but not in NKCC2-positive segments, suggesting differential effects of CUL3-Delta9. These results indicate that Cul3 haploinsufficiency does not cause FHHt, but dominant effects of CUL3-Delta9 are required. |
