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Title: Disruption of polycystin-1 cleavage leads to cardiac metabolic rewiring in mice
Authors: AMARAL, Andressa G.SILVA, Camille C. C. daSERNA, Julian D. C.HONORATO-SAMPAIO, KinulpeFREITAS, Jessica A.DUARTE-NETO, Amaro N.BLOISE, Antonio C.CASSINA, LauraYOSHINAGA, Marcos Y.CHAVES-FILHO, Adriano B.QIAN, FengMIYAMOTO, SayuriBOLETTA, AlessandraBORDIN, SilvanaKOWALTOWSKI, Alicia J.ONUCHIC, Luiz F.
Citation: BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE, v.1868, n.6, article ID 166371, 17p, 2022
Abstract: 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-proteincoupled 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-ACC beta, CPT1B-Cpt1b, Ppara, Nppa and Acta1. These findings suggested decreased fatty acid beta-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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Artigos e Materiais de Revistas Científicas - FM/MCM
Departamento de Clínica Médica - FM/MCM

Artigos e Materiais de Revistas Científicas - HC/ICHC
Instituto Central - HC/ICHC

Artigos e Materiais de Revistas Científicas - LIM/06
LIM/06 - Laboratório de Imunopatologia da Esquistossomose e outras Parasitoses

Artigos e Materiais de Revistas Científicas - LIM/29
LIM/29 - Laboratório de Nefrologia Celular, Genética e Molecular

Artigos e Materiais de Revistas Científicas - ODS/03
ODS/03 - Saúde e bem-estar

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