Cullin 3 mutant causing familial hyperkalemic hypertension lacks normal activity in the kidney

Yujiro Maeoka, Ryan J. Cornelius, Mohammed Zubaerul Ferdaus, Avika Sharma, Luan T. Nguyen, James A. McCormick

Research output: Contribution to journalArticlepeer-review

2 Scopus citations


Mutations in the ubiquitin ligase scaffold protein cullin 3 (CUL3) cause the disease familial hyperkalemic hypertension (FHHt). We recently reported that in the kidney, aberrant mutant CUL3 (CUL3-D9) activity lowers the abundance of CUL3-D9 and Kelch-like 3, the CUL3 substrate adaptor for with-no-lysine kinase 4 (WNK4) and that this is mechanistically important. However, whether CUL3-D9 exerts additional effects on other targets that may alter renal function is unclear. Here, we sought to determine 1) whether CUL3-D9 expression can rescue the phenotype of renal tubule-specific Cul3 knockout mice, and 2) whether CUL3-D9 expression affects other CUL3 substrates. Using an inducible renal tubule-specific system, we studied two CUL3-D9-expressing mouse models: Cul3 knockout (Cul3-/-/D9) and Cul3 heterozygous background (Cul3/D9, FHHt model). The effects of CUL3-D9 in these mice were compared with Cul3-/- and Cul3 mice. Similar to Cul3-/- mice, Cul3-/-/D9 mice displayed polyuria with loss of aquaporin 2 and collecting duct injury; proximal tubule injury also occurred. CUL3-D9 did not promote degradation of two CUL3 targets that accumulate in the Cul3-/- kidney: high-molecular-weight (HMW) cyclin E and NAD(P)H:quinone oxidoreductase 1 (NQO1) [a surrogate for the CUL3-Kelch-like ECH-associated protein 1 (KEAP1) substrate nuclear factor erythroid-2-related factor 2]. Since CUL3-D9 expression cannot rescue the Cul3-/- phenotype, our data suggest that CUL3-D9 cannot normally function in ubiquitin ligase complexes. In Cul3/D9 mice, KEAP1 abundance did not differ but NQO1 abundance was higher, suggesting adaptor sequestration by CUL3-D9 in vivo. Together, our results provide evidence that in the kidney, CUL3-D9 completely lacks normal activity and can trap CUL3 substrate adaptors in inactive complexes.

Original languageEnglish (US)
Pages (from-to)F564-F576
JournalAmerican Journal of Physiology - Renal Physiology
Issue number5
StatePublished - Nov 2022


  • aquaporin 2
  • cullin 3
  • cyclin E
  • familial hyperkalemic hypertension
  • nuclear factor erythroid-2-related factor

ASJC Scopus subject areas

  • Physiology
  • Urology


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