Faculty Collaboration Database

Mutant Cullin 3 causes familial hyperkalemic hypertension via dominant effects. JCI Insight 2017 Dec 21;2(24)

Date

12/22/2017

Pubmed ID

29263298

Pubmed Central ID

PMC5752287

DOI

10.1172/jci.insight.96700

Scopus ID

2-s2.0-85058719513 (requires institutional sign-in at Scopus site)   38 Citations

Abstract

Mutations in the ubiquitin ligase scaffold protein Cullin 3 (CUL3) cause the disease familial hyperkalemic hypertension (FHHt). In the kidney, mutant CUL3 (CUL3-Δ9) 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-Δ9 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-Δ9 (CUL3-Het/Δ9), using an inducible renal epithelial-specific system. Endogenous CUL3 was reduced to 50% in both models, and consistent with autoubiquitination, CUL3-Δ9 protein was undetectable in CUL3-Het/Δ9 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/Δ9 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-Δ9-mediated FHHt. WNK4 and SPAK localized to puncta in NCC-positive segments but not in NKCC2-positive segments, suggesting differential effects of CUL3-Δ9. These results indicate that Cul3 haploinsufficiency does not cause FHHt, but dominant effects of CUL3-Δ9 are required.

Author List

Ferdaus MZ, Miller LN, Agbor LN, Saritas T, Singer JD, Sigmund CD, McCormick JA

Author

Curt Sigmund PhD Chair, Professor in the Physiology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Blood Pressure
Cells, Cultured
Cullin Proteins
Epithelial Cells
Female
Haploinsufficiency
Heterozygote
Kidney
Male
Mice
Mutation
Phosphorylation
Potassium
Pseudohypoaldosteronism
Solute Carrier Family 12, Member 1
Solute Carrier Family 12, Member 3
Ubiquitination
Wnt4 Protein