Decreased Polycystin 2 Expression Alters Calcium-Contraction Coupling and Changes Beta-Adrenergic Signaling Pathways

Abstract

Cardiac disorders are the main cause of mortality in autosomal dominant polycystic kidney disease (ADPKD). However, how mutated 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. We found that 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 β-adrenergic receptor (βAR) agonist. Blockers of βAR-1 and 2 inhibited the ISO response in Pkd2+/− mice, suggesting that the dephosphorylated state of phospholamban is primarily by βAR-2 signaling. Importantly, the Pkd2+/− mice were normotensive and had no evidence of renal cysts. Our results showed that decreased PC2 levels shifted the βAR pathway balance and changed expression of calcium handling proteins, which resulted in altered cardiac contractility. We propose that PC2 levels in the heart directly contribute to cardiac remodeling in ADPKD patients in the absence of renal dysfunction.