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Disruption of polycystin-1 cleavage leads to cardiac metabolic rewiring in mice.
Amaral, Andressa G; da Silva, Camille C C; Serna, Julian D C; Honorato-Sampaio, Kinulpe; Freitas, Jéssica A; Duarte-Neto, Amaro N; Bloise, Antonio C; Cassina, Laura; Yoshinaga, Marcos Y; Chaves-Filho, Adriano B; Qian, Feng; Miyamoto, Sayuri; Boletta, Alessandra; Bordin, Silvana; Kowaltowski, Alicia J; Onuchic, Luiz F.
Afiliación
  • Amaral AG; Disciplinas de Nefrologia e Medicina Molecular, Departamento de Clínica Médica, Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP 01246903, Brazil.
  • da Silva CCC; Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, SP 05508000, Brazil.
  • Serna JDC; Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, SP 05508000, Brazil.
  • Honorato-Sampaio K; Faculdade de Medicina, Universidade Federal dos Vales do Jequitinhonha e Mucuri, Diamantina, MG 31270901, Brazil.
  • Freitas JA; Disciplinas de Nefrologia e Medicina Molecular, Departamento de Clínica Médica, Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP 01246903, Brazil.
  • Duarte-Neto AN; Disciplina de Emergências Clínicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP 01246903, Brazil.
  • Bloise AC; Departamento de Física Aplicada, Instituto de Física, Universidade de São Paulo, São Paulo, SP 05508000, Brazil.
  • Cassina L; Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milan 20132, Italy.
  • Yoshinaga MY; Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, SP 05508000, Brazil.
  • Chaves-Filho AB; Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, SP 05508000, Brazil.
  • Qian F; Division of Nephrology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
  • Miyamoto S; Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, SP 05508000, Brazil.
  • Boletta A; Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milan 20132, Italy.
  • Bordin S; Departamento de Fisiologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, SP 05508000, Brazil.
  • Kowaltowski AJ; Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, São Paulo, SP 05508000, Brazil.
  • Onuchic LF; Disciplinas de Nefrologia e Medicina Molecular, Departamento de Clínica Médica, Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP 01246903, Brazil. Electronic address: lonuchic@usp.br.
Biochim Biophys Acta Mol Basis Dis ; 1868(6): 166371, 2022 06 01.
Article en En | MEDLINE | ID: mdl-35218894
Cardiovascular manifestations account for marked morbi-mortality in autosomal dominant polycystic kidney disease (ADPKD). Pkd1- and Pkd2-deficient mice develop cardiac dysfunction, however the underlying mechanisms remain largely unclear. It is unknown whether impairment of polycystin-1 cleavage at the G-protein-coupled receptor proteolysis site, a significant ADPKD mutational mechanism, is involved in this process. We analyzed the impact of polycystin-1 cleavage on heart metabolism using Pkd1V/V mice, a model unable to cleave this protein and with early cardiac dysfunction. Pkd1V/V hearts showed lower levels of glucose and amino acids and higher lipid levels than wild-types, as well as downregulation of p-AMPK, p-ACCß, CPT1B-Cpt1b, Ppara, Nppa and Acta1. These findings suggested decreased fatty acid ß-oxidation, which was confirmed by lower oxygen consumption by Pkd1V/V isolated mitochondria using palmitoyl-CoA. Pkd1V/V hearts also presented increased oxygen consumption in response to glucose, suggesting that alternative substrates may be used to generate energy. Pkd1V/V hearts displayed a higher density of decreased-size mitochondria, a finding associated with lower MFN1, Parkin and BNIP3 expression. These derangements were correlated with increased apoptosis and inflammation but not hypertrophy. Notably, Pkd1V/V neonate cardiomyocytes also displayed shifts in oxygen consumption and p-AMPK downregulation, suggesting that, at least partially, the metabolic alterations are not induced by kidney dysfunction. Our findings reveal that disruption of polycystin-1 cleavage leads to cardiac metabolic rewiring in mice, expanding the understanding of heart dysfunction associated with Pkd1 deficiency and likely with human ADPKD.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Riñón Poliquístico Autosómico Dominante / Canales Catiónicos TRPP Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Revista: Biochim Biophys Acta Mol Basis Dis Año: 2022 Tipo del documento: Article País de afiliación: Brasil Pais de publicación: Países Bajos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Riñón Poliquístico Autosómico Dominante / Canales Catiónicos TRPP Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Revista: Biochim Biophys Acta Mol Basis Dis Año: 2022 Tipo del documento: Article País de afiliación: Brasil Pais de publicación: Países Bajos