Abstract Wed050: An ADPKD-Associated Pathway in Cardiac Homeostasis, Heart Failure, and Cardiovascular-kidney-metabolic

Bicaudal-C1 (Bicc1) is an RNA-binding protein essential for heart and kidney development. It plays a key role in autosomal dominant polycystic kidney disease (ADPKD), a common inherited kidney disorder that often leads to heart dysfunction, failure, and cardiovascular-kidney-metabolic (CKM) syndrome. In the kidney, Bicc1 interacts with two ADPKD-associated genes, Polycystin-1 (Pkd1) and Polycystin-2 (Pkd2). Both Pkd1 and Pkd2 regulate calcium cycling in cardiomyocytes, thereby maintaining cardiac function in adulthood. However, the role of Bicc1 in the postnatal heart and its involvement in heart failure (HF) beyond ADPKD-associated CKM remain unclear. To address this knowledge gap, we are investigating the role of Bicc1 in cardiac homeostasis and failure using gain- and loss-of-function approaches, next-generation sequencing, and the analysis of human heart failure (HF) patient samples. Our findings show that Bicc1 is highly expressed in neonatal and early postnatal mouse hearts, with its expression declining in adulthood but remaining detectable. Interestingly, in adult humans and mice, Bicc1 is predominantly expressed in cardiac fibroblasts, with low expression in cardiomyocytes. Moreover, in hearts from a surgically induced HF mouse model and in human patients with end-stage HF, Bicc1 expression is upregulated. Overexpression of Bicc1 in adult mouse hearts leads to decreased systolic function and exacerbated cardiac fibrosis in an HF model. Furthermore, preliminary data show reduced Pkd2 expression in the developing hearts of Bicc1 knockout mice, while Pkd1 expression remains unaffected. This suggests that Bicc1 regulates Pkd2 expression in the heart similarly to its function in the kidney. At the cellular level, transcriptomic analysis reveals the involvement of Bicc1 in cardiomyocyte contractility, calcium regulation, and extracellular matrix organization, as well as several novel pathways that, when disrupted, may contribute to HF progression. These findings demonstrate that Bicc1 plays a distinct role in cardiac dysfunction and failure, extending beyond its known role in ADPKD-related CKM.