Abstract 15380: Cardiac Localized Polycystin 2 is Required for Natriuretic Peptide Production and Its Absence is a Main Driver of Hypertension

Abstract

Introduction: Autosomal Dominant Polycystic Kidney Disease (ADPKD) occurs in 1:1000 births and causes renal cysts and loss of renal function. However, cardiovascular complications are the most common cause of mortality in ADPKD patients and hypertension affects 70% of patients before decline in renal function. ADPKD arises from mutations in PKD1 and PKD2, encoding Polycystin 1 and Polycystin 2 (PC2) respectively. PC2 forms a nonselective cation pore channel that conducts calcium. Heterozygous mice for Pkd2 have attenuated natriuretic peptide (NP) responses. The NPs, ANP and BNP, are regulators of euvolemia via renal excretion of sodium following cardiac atrial and ventricular stretch, thought to be a calcium activated process. We hypothesized cardiac PC2 contributes to NP production and loss of PC2 induces hypertension without renal involvement. Methods: Cardiomyocyte inducible PC2 KO (PC2 cKO) mice were generated by crossing Pkd2 floxed mice with αMHC-MerCreMer mice. Cardiomyocyte Cre expression was induced by tamoxifen diet at 6 weeks. Mice were aged to 7 months and had intra-aortic blood pressure monitoring or left ventricular tissue collection for quantitative PCR (qPCR) analysis. Male and female mice (n=4-9) were used and analyzed separately by Student’s t-Test, with a p <0.05 considered statistically significant. Results: PC2 cKO mice had elevated diurnal blood pressure (160/110mmHg) without renal cysts. Comparisons were made to age-matched controls. All reported genes were affected in males and females, with only female data reported (Mean ± SEM). qPCR analysis showed that PC2 cKO mice had a ~50% decrease in Nppa (WT: 1± 0.2 KO: 0.6 ± 0.1) and Nppb (WT: 1 ± 0.1 KO: 0.5 ± 0.2) mRNA, genes encoding ANP and BNP respectively. There was a ~60% reduction in Pcsk6 (WT: 1 ± 0.1, KO: 0.4 ± 0.1) mRNA in PC2 cKO mice, a gene encoding a protease necessary for Corin activity, regulating ANP. Cgb mRNA was abolished (WT: 1 ± 0.2, KO: 0.03 ± 0.01) in PC2 cKO mice, encoding Chromogranin B, a regulator of NF-κB mediated production of Nppb mRNA and ANP-containing vesicles. Conclusion: We conclude loss of PC2 in cardiomyocytes leads to a hypertensive phenotype which may arise from a calcium-dependent multi-component dysfunction of cardiomyocyte NP production.