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Metabolic Pathogenesis of Cardiac Dysfunction Associated with Pkd1 Deficiency in Mice

Grant number: 18/24846-0
Support type:Regular Research Grants
Duration: July 01, 2019 - December 31, 2021
Field of knowledge:Health Sciences - Medicine - Medical Clinics
Principal researcher:Luiz Fernando Onuchic
Grantee:Luiz Fernando Onuchic
Home Institution: Faculdade de Medicina (FM). Universidade de São Paulo (USP). São Paulo , SP, Brazil


Autosomal dominant polycystic kidney disease (ADPKD) is the most common life-threatening monogenic human illness, with an estimated prevalence of 1:1000. This disease is essentially caused by mutation in the PKD1 (Polycystic Kidney Disease 1) or PKD2 genes. Most cases arise from mutations in PKD1. Although the renal phenotype prevails in this disorder, with 70% of the patients requiring renal replacement therapy by 70 years of age, cardiovascular involvement initiates early and is the main cause of mortality. ADPKD is associated with increased left ventricular mass and development of idiopathic dilated cardiomyopathy, however the pathogenesis of this phenotype was poorly understood until recently. A capital, recent study from our group, however, revealed that Pkd1-haploinsufficient mice, noncystic and normotensive, presented systolic dysfunction and decreased myocardial deformability, while Pkd1-deficient cystic hypertensive mice displayed not only such abnormalities but also diastolic dysfunction. These results strongly support a primary role for PKD1 deficiency in cardiac dysfunction associated with ADPKD, whereas suggest that elevation in blood pressure can worsen this phenotype with age. In parallel, studies performed in the last years showed that metabolic cellular alterations are central in the pathogenesis of renal disease in ADPKD, including increased glucose consumption preferentially associated with aerobic glycolysis and alterations in beta-oxidation of fatty acids and oxidative phosphorylation. Such findings were accompanied by mitochondrial abnormalities in renal cyst-lining cells. In this scenario, we hypothesized that cardiomyocytes may also present metabolic alterations relevant in ADPKD, contributing to cardiac dysfunction. In this project, therefore, we will investigate the potential cellular metabolic basis of this dysfunction pathogenesis. To achieve this goal, we will evaluate a series of distinct representative parameters of cardiac energetic metabolism in a mouse model homozygous for a Pkd1 hypomorphic allele and severely cystic, also with systolic dysfunction, having wild-type animals as their controls. Our specific aims will include: 1) determination of heart weight/body weight ratio; 2) measurement of cardiomyocyte size; 3) evaluation of expression profiles of proteins potentially involved in the cardiac metabolic dysfunction associated with ADPKD; 4) analysis of expression profiles of proteins potentially involved in abnormal calcium cycling in cardiomyocyte; 5) evaluation of cytoplasmic mitochondrial volumetric density in cardiac tissue; 6) performance of morphometric mitochondrial analyses in heart tissue; 7) evaluation of expression profiles of proteins involved in mitochondrial fusion and fission in cardiac tissue; 8) performance of semiquantitative assay of mitochondrial DNA copy number normalized to nuclear DNA in cardiac tissue; 9) evaluation of oxygen consumption rate in cardiomyocytes in response to different substrates and challenges; and 10) analyses of metabolomic and lipidomic profiles in cardiomyocytes. Depending on our results, our aims will include evaluation of therapeutic potential of agents capable of modulating cardiomyocyte cellular metabolism on these animals' cardiac phenotype. (AU)

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