Mutant Cullin 3 causes familial hyperkalemic hypertension via dominant effects
| Autor: | Lauren N. Miller, Mohammed Z. Ferdaus, Jeffrey D. Singer, Turgay Saritas, Larry N. Agbor, James A. McCormick, Curt D. Sigmund |
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| Rok vydání: | 2019 |
| Předmět: |
Male
0301 basic medicine Heterozygote 110312 Nephrology and Urology Pseudohypoaldosteronism Blood Pressure Haploinsufficiency Protein Serine-Threonine Kinases Kidney medicine.disease_cause Mice 03 medical and health sciences Wnt4 Protein medicine Animals Solute Carrier Family 12 Member 3 Phosphorylation Cells Cultured Solute Carrier Family 12 Member 1 Mutation biology Kinase Chemistry urogenital system FOS: Clinical medicine Ubiquitination Kidney metabolism Epithelial Cells General Medicine Cullin Proteins Molecular biology WNK4 Ubiquitin ligase 030104 developmental biology medicine.anatomical_structure Potassium biology.protein Female Cotransporter Research Article |
| DOI: | 10.25376/hra.7800926 |
| Popis: | 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 WNK4and 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-positivesegments 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. |
| Databáze: | OpenAIRE |
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