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Role of KLHL3 and dietary K+ in regulating KS-WNK1 expression.
Ostrosky-Frid, Mauricio; Chávez-Canales, María; Zhang, Jinwei; Andrukhova, Olena; Argaiz, Eduardo R; Lerdo-de-Tejada, Fernando; Murillo-de-Ozores, Adrian; Sanchez-Navarro, Andrea; Rojas-Vega, Lorena; Bobadilla, Norma A; Vazquez, Norma; Castañeda-Bueno, María; Alessi, Dario R; Gamba, Gerardo.
Afiliação
  • Ostrosky-Frid M; Molecular Physiology Unit, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City, Mexico.
  • Chávez-Canales M; PECEM (MD/PhD), Facultad de Medicina, Universidad Nacional Autónoma de México, Mexico City, Mexico.
  • Zhang J; Unidad de Investigación UNAM-INC, Instituto Nacional de Cardiología Ignacio Chávez and Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City, Mexico.
  • Andrukhova O; Institute of Biomedical and Clinical Sciences, Medical School, College of Medicine and Health, University of Exeter, Hatherly Laboratories, Exeter, United Kingdom.
  • Argaiz ER; MRC Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences, University of Dundee, Dundee, United Kingdom.
  • Lerdo-de-Tejada F; Molecular Physiology Unit, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City, Mexico.
  • Murillo-de-Ozores A; Unidad de Investigación UNAM-INC, Instituto Nacional de Cardiología Ignacio Chávez and Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City, Mexico.
  • Sanchez-Navarro A; Facultad de Medicina, Universidad Nacional Autónoma de México, Mexico City, Mexico.
  • Rojas-Vega L; Department of Nephrology and Mineral Metabolism, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico.
  • Bobadilla NA; Molecular Physiology Unit, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City, Mexico.
  • Vazquez N; Department of Nephrology and Mineral Metabolism, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico.
  • Castañeda-Bueno M; Department of Nephrology and Mineral Metabolism, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico.
  • Alessi DR; Molecular Physiology Unit, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City, Mexico.
  • Gamba G; Department of Nephrology and Mineral Metabolism, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico.
Am J Physiol Renal Physiol ; 320(5): F734-F747, 2021 05 01.
Article em En | MEDLINE | ID: mdl-33682442
The physiological role of the shorter isoform of with no lysine kinase (WNK)1 that is exclusively expressed in the kidney (KS-WNK1), with particular abundance in the distal convoluted tubule, remains elusive. KS-WNK1, despite lacking the kinase domain, is nevertheless capable of stimulating the NaCl cotransporter, apparently through activation of WNK4. It has recently been shown that a less severe form of familial hyperkalemic hypertension featuring only hyperkalemia is caused by missense mutations in the WNK1 acidic domain that preferentially affect cullin 3 (CUL3)-Kelch-like protein 3 (KLHL3) E3-induced degradation of KS-WNK1 rather than that of full-length WNK1. Here, we show that full-length WNK1 is indeed less impacted by the CUL3-KLHL3 E3 ligase complex compared with KS-WNK1. We demonstrated that the unique 30-amino acid NH2-terminal fragment of KS-WNK1 is essential for its activating effect on the NaCl cotransporter and recognition by KLHL3. We identified specific amino acid residues in this region critical for the functional effect of KS-WNK1 and KLHL3 sensitivity. To further explore this, we generated KLHL3-R528H knockin mice that mimic human mutations causing familial hyperkalemic hypertension. These mice revealed that the KLHL3 mutation specifically increased expression of KS-WNK1 in the kidney. We also observed that in wild-type mice, the expression of KS-WNK1 was only detectable after exposure to a low-K+ diet. These findings provide new insights into the regulation and function of KS-WNK1 by the CUL3-KLHL3 complex in the distal convoluted tubule and indicate that this pathway is regulated by dietary K+ levels.NEW & NOTEWORTHY In this work, we demonstrated that the kidney-specific isoform of with no lysine kinase 1 (KS-WNK1) in the kidney is modulated by dietary K+ and activity of the ubiquitin ligase protein Kelch-like protein 3. We analyzed the role of different amino acid residues of KS-WNK1 in its activity against the NaCl cotransporter and sensitivity to Kelch-like protein 3.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Pseudo-Hipoaldosteronismo / Potássio na Dieta / Proteínas Adaptadoras de Transdução de Sinal / Proteína Quinase 1 Deficiente de Lisina WNK / Rim / Proteínas dos Microfilamentos Tipo de estudo: Prognostic_studies Limite: Animals Idioma: En Revista: Am J Physiol Renal Physiol Ano de publicação: 2021 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Pseudo-Hipoaldosteronismo / Potássio na Dieta / Proteínas Adaptadoras de Transdução de Sinal / Proteína Quinase 1 Deficiente de Lisina WNK / Rim / Proteínas dos Microfilamentos Tipo de estudo: Prognostic_studies Limite: Animals Idioma: En Revista: Am J Physiol Renal Physiol Ano de publicação: 2021 Tipo de documento: Article