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Combined Kelch-like 3 and Cullin 3 Degradation is a Central Mechanism in Familial Hyperkalemic Hypertension in Mice.
Maeoka, Yujiro; Ferdaus, Mohammed Z; Cornelius, Ryan J; Sharma, Avika; Su, Xiao-Tong; Miller, Lauren N; Robertson, Joshua A; Gurley, Susan B; Yang, Chao-Ling; Ellison, David H; McCormick, James A.
Afiliación
  • Maeoka Y; Division of Nephrology and Hypertension, Department of Medicine, Oregon Health & Science University, Portland, Oregon.
  • Ferdaus MZ; Division of Nephrology and Hypertension, Department of Medicine, Oregon Health & Science University, Portland, Oregon.
  • Cornelius RJ; Division of Nephrology and Hypertension, Department of Medicine, Oregon Health & Science University, Portland, Oregon.
  • Sharma A; Division of Nephrology and Hypertension, Department of Medicine, Oregon Health & Science University, Portland, Oregon.
  • Su XT; Division of Nephrology and Hypertension, Department of Medicine, Oregon Health & Science University, Portland, Oregon.
  • Miller LN; Division of Nephrology and Hypertension, Department of Medicine, Oregon Health & Science University, Portland, Oregon.
  • Robertson JA; Division of Nephrology and Hypertension, Department of Medicine, Oregon Health & Science University, Portland, Oregon.
  • Gurley SB; Division of Nephrology and Hypertension, Department of Medicine, Oregon Health & Science University, Portland, Oregon.
  • Yang CL; Division of Nephrology and Hypertension, Department of Medicine, Oregon Health & Science University, Portland, Oregon.
  • Ellison DH; Division of Nephrology and Hypertension, Department of Medicine, Oregon Health & Science University, Portland, Oregon.
  • McCormick JA; Veterans Affairs Portland Healthcare System, Portland, Oregon.
J Am Soc Nephrol ; 33(3): 584-600, 2022 03.
Article en En | MEDLINE | ID: mdl-35064051
BACKGROUND: Mutations in the ubiquitin ligase scaffold protein Cullin 3 (CUL3) gene cause the disease familial hyperkalemic hypertension (FHHt). In the kidney, mutant CUL3 (CUL3-Δ9) increases abundance of With-No-Lysine (K) Kinase 4 (WNK4), inappropriately activating sterile 20/SPS-1-related proline/alanine-rich kinase (SPAK), which then phosphorylates and hyperactivates the Na+Cl- cotransporter (NCC). The precise mechanism by which CUL3-Δ9 causes FHHt is unclear. We tested the hypothesis that reduced abundance of CUL3 and of Kelch-like 3 (KLHL3), the CUL3 substrate adaptor for WNK4, is mechanistically important. Because JAB1, an enzyme that inhibits CUL3 activity by removing the ubiquitin-like protein NEDD8, cannot interact with CUL3-Δ9, we also determined whether Jab1 disruption mimicked the effects of CUL3-Δ9 expression. METHODS: We used an inducible renal tubule-specific system to generate several mouse models expressing CUL3-Δ9, mice heterozygous for both CUL3 and KLHL3 (Cul3+/-/Klhl3+/- ), and mice with short-term Jab1 disruption (to avoid renal injury associated with long-term disruption). RESULTS: Renal KLHL3 was higher in Cul3-/- mice, but lower in Cul3-/-/Δ9 mice and in the Cul3+/-/Δ9 FHHt model, suggesting KLHL3 is a target for both WT and mutant CUL3. Cul3+/-/Klhl3+/- mice displayed increased WNK4-SPAK activation and phospho-NCC abundance and an FHHt-like phenotype with increased plasma [K+] and salt-sensitive blood pressure. Short-term Jab1 disruption in mice lowered the abundance of CUL3 and KLHL3 and increased the abundance of WNK4 and phospho-NCC. CONCLUSIONS: Jab1-/- mice and Cul3+/-/Klhl3+/- mice recapitulated the effects of CUL3-Δ9 expression on WNK4-SPAK-NCC. Our data suggest degradation of both KLHL3 and CUL3 plays a central mechanistic role in CUL3-Δ9-mediated FHHt.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Seudohipoaldosteronismo / Proteínas Cullin / Hipertensión Límite: Animals / Female / Humans / Male Idioma: En Revista: J Am Soc Nephrol Asunto de la revista: NEFROLOGIA Año: 2022 Tipo del documento: Article Pais de publicación: Estados Unidos

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Seudohipoaldosteronismo / Proteínas Cullin / Hipertensión Límite: Animals / Female / Humans / Male Idioma: En Revista: J Am Soc Nephrol Asunto de la revista: NEFROLOGIA Año: 2022 Tipo del documento: Article Pais de publicación: Estados Unidos