| First Author | Amaral AG | Year | 2022 |
| Journal | Biochim Biophys Acta Mol Basis Dis | Volume | 1868 |
| Issue | 6 | Pages | 166371 |
| PubMed ID | 35218894 | Mgi Jnum | J:322828 |
| Mgi Id | MGI:7259689 | Doi | 10.1016/j.bbadis.2022.166371 |
| Citation | Amaral AG, et al. (2022) Disruption of polycystin-1 cleavage leads to cardiac metabolic rewiring in mice. Biochim Biophys Acta Mol Basis Dis 1868(6):166371 |
| abstractText | 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 Pkd1(V/V) mice, a model unable to cleave this protein and with early cardiac dysfunction. Pkd1(V/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-ACCbeta, CPT1B-Cpt1b, Ppara, Nppa and Acta1. These findings suggested decreased fatty acid beta-oxidation, which was confirmed by lower oxygen consumption by Pkd1(V/V) isolated mitochondria using palmitoyl-CoA. Pkd1(V/V) hearts also presented increased oxygen consumption in response to glucose, suggesting that alternative substrates may be used to generate energy. Pkd1(V/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, Pkd1(V/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. |
