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

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...

Full description

Saved in:
Bibliographic Details
Published in:Biochimica et biophysica acta. Molecular basis of disease 2022-06, Vol.1868 (6), p.166371-166371, Article 166371
Main Authors: 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.
Format: Article
Language:English
Subjects:
Animals
Autosomal dominant polycystic kidney disease
Cardiac dysfunction
Heart
Lipid derangement
Metabolic rewiring
Mice
Mitochondria
Mitochondria - metabolism
Mutation
Polycystic Kidney, Autosomal Dominant - genetics
Polycystic Kidney, Autosomal Dominant - metabolism
Polycystin-1 cleavage at GPS
TRPP Cation Channels - genetics
TRPP Cation Channels - metabolism
Citations: Items that this one cites
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:0925-4439
1879-260X
DOI:10.1016/j.bbadis.2022.166371