Disruption of polycystin-1 cleavage leads to cardiac metabolic rewiring in mice

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art_AMARAL_Disruption_of_polycystin1_cleavage_leads_to_cardiac_metabolic_2022.PDF (10.71 MB)
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0
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article
Data de publicação
2022
DOI
Scopus
Web of Science
PubMed
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Título do Volume
Editora
ELSEVIER
Autores
SILVA, Camille C. C. da
SERNA, Julian D. C.
HONORATO-SAMPAIO, Kinulpe
BLOISE, Antonio C.
CASSINA, Laura
YOSHINAGA, Marcos Y.
CHAVES-FILHO, Adriano B.
Citação
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE, v.1868, n.6, article ID 166371, 17p, 2022
Projetos de Pesquisa
Unidades Organizacionais
Fascículo
Resumo
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.
Palavras-chave
Autosomal dominant polycystic kidney disease, Polycystin-1 cleavage at GPS, Cardiac dysfunction, Metabolic rewiring, Mitochondria, Lipid derangement
URI
https://observatorio.fm.usp.br/handle/OPI/47025
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Artigos e Materiais de Revistas Científicas - FM/MCM
Artigos e Materiais de Revistas Científicas - HC/ICHC
Artigos e Materiais de Revistas Científicas - LIM/06
Artigos e Materiais de Revistas Científicas - LIM/29
Artigos e Materiais de Revistas Científicas - ODS/03