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

Key Points Cardiac localized polycystin facilitates natriuretic peptide signaling pathways. Hypertension associated with autosomal dominant polycystic kidney disease may arise from impaired cardiac natriuretic peptide signaling. Background Hypertension is seen in 70% of patients with autosomal dominant polycystic kidney disease by age of 30 years before 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 knockout models of polycystin-2 (cPC2-KO) mice and Cre control littermates were conducted. Complementary studies were conducted in ex vivo murine hearts, engineered heart tissue with human iPSCs driven into cardiomyocytes with CRISPR/Cas9 knockout of PKD2 and in in vitro cell lines. Results cPC2-KO mice demonstrated diurnal hypertension. Circulating atrial natriuretic peptide (ANP) and brain natriuretic peptide 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 chromogranin B, 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 autosomal dominant polycystic kidney disease. Podcast This article contains a podcast at https://dts.podtrac.com/redirect.mp3/www.asn-online.org/media/podcast/JASN/2024_10_08_ASN0000000000000490.mp3