Cardiac Localized Polycystin-2 in the Natriuretic Peptide Signaling Pathway and Hypertension

Background: Hypertension is seen in 70% of autosomal dominant polycystic kidney disease (ADPKD) patients by the age of 30 prior to decline in kidney function. However, cardiac origins of hypertension, such as the natriuretic peptide signaling pathway, have not been fully investigated. We hypothesized that cardiomyocyte-localized polycystin proteins contribute to production of natriuretic peptides, and loss of this pathway would contribute to hypertension. Methods: Telemetry, echocardiography, and a molecular analysis of the natriuretic peptide pathway from left-ventricular tissue of cardiomyocyte-specific knock-out models of polycystin-2 (cPC2-KO) mice and Cre control littermates was conducted. Complementary studies were conducted in ex-vivo murine hearts, engineered heart tissue with human iPSCs driven into cardiomyocytes with CRISPR/Cas9 KO of PKD2 and in in-vitro cell lines. Results: cPC2-KO mice demonstrated diurnal hypertension. Circulating ANP and BNP were unchanged between cPC2-KO and Cre mice. Analysis of the pathways involved in production, maturation, and activity of natriuretic peptides identified decreased transcription of CgB, PCSK6, NPR1 and NFAT genes in cPC2-KOs. Human iPSC-derived cardiomyocytes with PC2-KO failed to produce ANP. Re-expression of polycystin-2 in a myoblast cell line, but not pathogenic forms of polycystin-2, restored ANP production. Conclusions: Natriuretic peptide production required cardiac localized polycystin-2 and loss of this pathway may contribute to the development of hypertension in ADPKD.