Abstract 4369533: Loss of Polycystin-1 Enhances Cardiomyocyte Beta-Adrenergic Signaling

Abstract

Introduction: Cardiovascular disease is the leading cause of death among individuals with Autosomal Dominant Polycystic Kidney Disease (ADPKD). While these conditions are often attributed to ADPKD-related hypertension, alterations in Polycystin-1 (PC1) directly affect cardiomyocyte function, and cardiac alterations have been observed in ADPKD patients with normal renal function, suggesting a direct role of PC1 in cardiac cells. Goal: To elucidate the contribution of PC1 deficiency to cardiac dysfunction, we performed RNA-seq in cardiac tissues and isolated cardiomyocytes from WT (F/F) and cardiomyocyte-specific PC1 knockout mice model (CKO; F/F αMHC-Cre). Methods: Bulk RNA-seq was performed using heart tissue and isolated adult cardiomyocytes from WT and CKO mice (2-4 months old). Ca 2+ and contractility were measured using an IonOptix imaging system before and after isoproterenol stimulation. Results: Bulk RNA-seq analysis of heart tissue revealed modest changes in gene expression (15 downregulated and 12 upregulated genes), primarily affecting β-adrenergic and cAMP signaling pathways, as identified using Ingenuity Pathway Analysis (IPA) software ( Qiagen ). RNA-seq of isolated CKO cardiomyocytes revealed a larger number of differentially expressed genes (59 downregulated and 91 upregulated) compared to WT. IPA analysis identified the most upregulated pathways as cardiac β-adrenergic signaling, cAMP/protein kinase A, and the apelin cardiomyocyte signaling pathway. These findings correlate with previous observations where renal PC1-defective cells have increased cAMP/PKA signaling. To investigate whether PC1 deficiency enhances β-adrenergic signaling, we conducted pilot studies using isolated adult cardiomyocytes from WT and CKO mice. As expected, CKO cardiomyocytes exhibited impaired Ca 2+ transient and contractility. Isoproterenol stimulation increased Ca 2+ transient amplitude and contraction peak in WT cardiomyocytes. Interestingly, isoproterenol elicited a normal response in CKO cardiomyocytes, restoring function to levels comparable to isoproterenol-stimulated WT levels. Conclusions: Our data suggest that β-adrenergic signaling is augmented in PC1-deficient cardiomyocytes. This augmentation can restore functionality in these cells, but potentially at the expense of cardiac reserve. Over time, such adaptations may lead to detrimental remodeling, suggesting a trade-off between immediate functional restoration and long-term structural integrity of the heart.