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Kidney Week

Abstract: PO1508

Cardiac Dysfunction in Pkd1-Deficient Mice Is Associated with Metabolic Rewiring

Session Information

Category: Genetic Diseases of the Kidneys

  • 1001 Genetic Diseases of the Kidneys: Cystic

Authors

  • Amaral, Andressa G., Universidade de Sao Paulo, Sao Paulo, São Paulo, Brazil
  • Silva, Camille C. C., Universidade de Sao Paulo, Sao Paulo, São Paulo, Brazil
  • Sampaio, Kinulpe H., Universidade Federal dos Vales do Jequitinhonha e Mucuri, Diamantina, MG, Brazil
  • Duarte-Neto, Amaro N., Universidade de Sao Paulo, Sao Paulo, São Paulo, Brazil
  • Bloise, Antonio C., Universidade de Sao Paulo, Sao Paulo, São Paulo, Brazil
  • Cassina, Laura, IRCCS Ospedale San Raffaele, Milano, Lombardia, Italy
  • Boletta, Alessandra, IRCCS Ospedale San Raffaele, Milano, Lombardia, Italy
  • Chaves-Filho, Adriano B., Universidade de Sao Paulo, Sao Paulo, São Paulo, Brazil
  • Yoshinaga, Marcos Y., Universidade de Sao Paulo, Sao Paulo, São Paulo, Brazil
  • Miyamoto, Sayuri, Universidade de Sao Paulo, Sao Paulo, São Paulo, Brazil
  • Bordin, Silvana A., Universidade de Sao Paulo, Sao Paulo, São Paulo, Brazil
  • Kowaltowski, Alicia J., Universidade de Sao Paulo, Sao Paulo, São Paulo, Brazil
  • Onuchic, Luiz F., Universidade de Sao Paulo, Sao Paulo, São Paulo, Brazil
Background

Myocardial abnormalities are associated with significant clinical burden in ADPKD but the underlying pathogenesis is still largely unclear.

Methods

We investigated the metabolic basis of the ADPKD-associated cardiac phenotype using a mouse homozygous for a Pkd1 hypomorphic allele that prevents PC1 cleavage (VV) with early cardiac dysfunction.

Results

VV hearts displayed metabolome and lipidome signatures associated with lower levels of glucose and amino acids (aa) and higher levels of lipid species than wild-type (WT) hearts. This VV profile also included decreased Cpt1b (-28±12%, p<0.05, Pparα (-26±12%, p<0.05), PGC1α (-22±8.4%, p<0.05), phospho-AMPK (-46±12%, p<0.01) and phospho-ACCβ (-35±15%, p<0.05) expression, indicating downregulation of fatty acid oxidation and lipotoxicity. Mitochondrial density was higher in VV than WT hearts (49.5±1.8% vs 41.3±3.0%, p<0.01) and size was smaller, but shape descriptors and MFN2 and DRP1 expression did not differ. Structural changes were followed by increased cardiac oxygen consumption in response to glucose (928±157 vs 762±104pmolO2/min/mg, p<0.05). Notably, VV neonate cardiomyocytes showed higher mitochondrial maximal respiration than WTs (327±24 vs 216±64pmolO2/min, p<0.01) and a trend of increased basal respiration (p=0.09). These data suggest that glucose and aa may be preferably used as energy substrate in VV hearts. Cardiac expression of fetal genes Nppa and Acta1 were also increased (3.35±1.54 vs 1.10±0.54 AU, p<0.01 and 2.26±0.94 vs 1.07±0.38 AU, p<0.01, respectively), revealing inappropriate transcriptional transition to the mature state. Unlike Pkd1-deficient kidneys, phospho-RPS6 is downregulated in VV hearts (-58±15%, p<0.01) and glucose is not targeted for aerobic glycolysis, since lactate levels were reduced. These metabolic changes correlated with increased cardiac apoptosis and inflammation but not with hypertrophic remodeling.

Conclusion

Our findings uncover a cardiac metabolic rewiring associated with Pkd1 deficiency, revealing a pattern only partially similar to the metabolic profile observed in the cystic kidney phenotype. These data conceptually expand the understanding of heart dysfunction associated with Pkd1 deficiency and likely ADPKD.

Funding

  • Government Support - Non-U.S.