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Polycystin 2 expression alters calcium‐contraction coupling

Cardiac disorders are the main cause of mortality in autosomal dominant polycystic kidney disease (ADPKD). However, how the mutations in the polycystins predispose ADPKD patients to cardiac pathologies before development of renal dysfunction is unknown. We investigate the effect of decreased polycystin 2 (PC2) levels, a calcium channel that interacts with the ryanodine receptor, on myocardial function. We hypothesize that heterozygous PC2 mice (Pkd2+/‐) undergo cardiac remodeling due to changes in calcium handling, separate to renal complications. Pkd2+/‐ cardiomyocytes have altered calcium handling, independent of desensitized calcium‐contraction coupling. Paradoxically, in Pkd2+/‐ mice, PKA phosphorylation of phospholamban was decreased, whereas PKA phosphorylation of troponin I was increased, explaining the decoupling between calcium signaling and contractility. In silico modeling supported this relationship. Echocardiography measurements showed that Pkd2+/‐ mice have increased left ventricular ejection fraction after stimulation with isoproterenol (ISO), a ß‐adrenergic receptor (ßAR) agonist. Importantly, the Pkd2+/‐ mice were normotensive and had no evidence of renal cysts. In contrast to the Pkd2+/‐ mice, Pkd2 overexpression mice had decreased ejection fraction in response to isoproternol. Our results showed that PC2 levels change expression of calcium handling proteins, which resulted in altered cardiac contractility. Moreover, we observed alterations in the ß‐adrenergic receptor signaling pathway. We propose that PC2 levels in the heart directly contribute to cardiac remodeling in ADPKD patients in the absence of renal dysfunction.