Abstract P464: Cardiac Dysfunction In A Mouse Model For Autosomal Dominant Polycystic Kidney Disease

Mutations in polycystin-1 (PC1) cause autosomal dominant polycystic kidney disease (ADPKD), a disorder that manifests with cardiac hypertrophy and dysfunction. We recently showed that cardiomyocyte-specific PC1 KO mice exhibit both systolic and diastolic dysfunction without signs of cardiac hypertrophy. The purpose of this study was to determine the effects of ADPKD-causing PC1 mutations on cardiac function using a mouse model for ADPKD harboring a mutation in PC1 R3277C (RC/RC). We used echocardiography to determine cardiac function and Western blot analysis to explore signaling pathways in WT and RC/RC mice (2-4 months of age).We observed a slight but significant decrease in ejection fraction (77.2±0.7 vs 86.2±2.4 %, N=5, 4, P=0.015) without signs of left ventricular hypertrophy (LV mass 78.4±5.5 vs 93.5±4.2 mg, N=5, 4, P>0.05) in RC/RC compared to WT mice. Western blot analysis from total heart lysates (WT and RC/RC; N=5) revealed no changes in protein levels of hypertrophic markers: beta myosin heavy chain (β-MHC) and regulator of calcineurin 1 (RCAN1). In addition, we studied multiple signaling pathways involved in cardiac hypertrophy by analyzing their phosphorylation status by Western blot (phosphorylated/total protein). We observed no changes in mTOR, S6K1 and S6 phosphorylation. However, a decrease in p-4EBP1 and p-eIF4B was observed in RC/RC compared to WT. Moreover, we observed a significant increase in p-ERK and p-CaMKII. Our data suggest that alterations in PC1 signaling promote cardiac dysfunction but do not promote hypertrophy in young mice (2-4 months of age). Published evidence (PMID: 32730856) suggest that RC/RC hearts become hypertrophic at 6 months of age. However, our data suggest there may be dysfunction prior to cardiac hypertrophy. This warrants further investigation into the more primary role of ADPKD-associated co-morbidities. More studies, with a larger animal cohort, are necessary to unveil the effects of mutant PC1 on cardiac function.