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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.
Biochimica et biophysica acta. Molecular basis of disease, 06/2022, Volume: 1868, Issue: 6Journal Article
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-ACCβ, CPT1B-Cpt1b, Ppara, Nppa and Acta1. These findings suggested decreased fatty acid β-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. Display omitted •Germline disruption of PC1 cleavage leads to cardiac metabolic rewiring in mice.•Lack of cleaved PC1 is associated with specific metabolome and lipidome signatures.•This deficiency increases mitochondria density and glucose-based oxygen consumption.•Fatty acid oxidation is reduced but Warburg effect and mTOR upregulation do not occur.•Hearts lacking PC1 cleavage show a metabolic pattern partly similar to cystic kidneys.
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