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

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Amaral, Andressa G. ; da Silva, Camille C. C. ; Serna, Julian D. C. ; Honorato-Sampaio, Kinulpe ; Freitas, Jessica 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.

• Document type: Journal article
• Source: BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE; v. 1868, n. 6, p. 17-pg., 2022-03-04.

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. (AU)

• FAPESP's process: 13/07937-8 - Redoxome - Redox Processes in Biomedicine
• Grantee: Ohara Augusto
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC
• FAPESP's process: 15/17152-3 - Smoking Effects on the Renal and Cardiac Phenotypes in Cystic Mice due to Pkd1 Inactivation
• Grantee: Luiz Fernando Onuchic
• Support Opportunities: Regular Research Grants
• FAPESP's process: 18/24846-0 - Metabolic Pathogenesis of Cardiac Dysfunction Associated with Pkd1 Deficiency in Mice
• Grantee: Luiz Fernando Onuchic
• Support Opportunities: Regular Research Grants