Date of Award

Winter 12-8-2025

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Physiology

First Advisor

Ivana Kuo

Abstract

Patients with autosomal polycystic kidney disease (ADPKD) have an increased risk and worse outcomes after acute myocardial infarction, but the mechanism for this is unknown. Polycystin 2 (PC2), one of the two main proteins mutated in ADPKD, is a calcium permeant channel that localizes to the ER/SR. In non-cardiac cells, PC2 regulates the unfolded protein response (UPR) pathway under ER stress. However, whether PC2 is cardioprotective against ER stress is unknown. We found that PC2 expression increased in cardiomyocytes from human ischemic hearts and infarcted murine hearts. Cardiomyocyte-specific PC2 KO (PC2 KO) mice had worsened cardiac function after myocardial infarction (MI) compared to control (CTL) mice. The UPR arm PERK and its downstream target CHOP were decreased in PC2 KO mice and myoblast PC2 KO cells. The ER stress activator tunicamycin increased ER calcium leak and mitochondrial calcium in CTL cells, but not in PC2 KO cells or isolated PC2 KO cardiomyocytes. Consequently, there was impaired mitochondrial membrane potential and increased cell death in PC2 KO cells. Tunicamycin induced a rapid increase in PC2 expression with enhanced localization to ER-mitochondrial contact sites. Importantly, restoration of functional PC2 in vitro enhanced PERK phosphorylation and the calcium leak in PC2 KO cells. These data suggest that the upregulation of PC2 with ER stress facilitates its function as a leak channel under ER stress, regulating UPR-mitochondrial crosstalk in the early adaptive phase of ER stress. Loss of PC2 impairs the early adaptation and results in worsened cardiac dysfunction with AMI.

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