Mutant Cullin 3 Causes Familial Hyperkalemic Hypertension Via Dominant Effects
Funding for this project was provided by NIH grants R01DK098141 to JAM, R01HL125603 to CDS, and R01DK051496 to JDS; a fellowship from the German research Foundation (DFG - Forschungsstipendium; 332853055) to TS, and American Heart Association Postdoctoral Fellowship 17POST33670206 to MZF.
Journal of Clinical Investigation Insight
Mutations in the ubiquitin ligase scaffold protein Cullin 3 (CUL3) cause the disease familial hyperkalemic hypertension (FHHt). In the kidney, mutant CUL3 (CUL3-?9) 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-?9 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-?9 (CUL3-Het/?9), using an inducible renal epithelial–specific system. Endogenous CUL3 was reduced to 50% in both models, and consistent with autoubiquitination, CUL3-?9 protein was undetectable in CUL3-Het/?9 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/?9 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-?9–mediated FHHt. WNK4 and SPAK localized to puncta in NCC-positive segments but not in NKCC2-positive segments, suggesting differential effects of CUL3-?9. These results indicate that Cul3 haploinsufficiency does not cause FHHt, but dominant effects of CUL3-?9 are required.
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Ferdaus, M. et al. 2017. Mutant Cullin 3 causes familial hyperkalemic hypertension via dominant effects, The Journal of Clinical Ivestigation Insight, 2(24).