(Pro)renin receptor promotes cardiomyocyte senescence via tripartite motif-containing 24-mediated stabilization of p53 in diabetic cardiomyopathy

Abstract

Diabetic cardiomyopathy (DCM) is a major complication of diabetes and a leading contributor to heart failure, in which cardiomyocyte senescence plays an increasingly recognized role. However, the underlying mechanisms driving this process remain poorly defined. Here, we identify the (pro)renin receptor (PRR) as a critical mediator of cardiomyocyte senescence in DCM. Using a high-fat diet and streptozotocin (STZ)-induced DCM mouse model, as well as primary cardiomyocytes exposed to high glucose and palmitic acid, we demonstrate that PRR expression is significantly upregulated in diabetic hearts and closely associated with key senescence markers, including SA-β-gal, γ-H2AX, p16, and p21. PRR overexpression exacerbates these senescence phenotypes and promotes the secretion of profibrotic senescence-associated secretory phenotype factors, contributing to increased myocardial fibrosis and cardiac dysfunction. Mechanistically, PRR stabilizes the p53 protein by inhibiting tripartite motif-containing 24 (TRIM24)-mediated ubiquitination and proteasomal degradation, thereby activating the p53-p21 axis. These findings reveal a novel role of the PRR in diabetic myocardial senescence and provide potential therapeutic targets for attenuating DCM progression.

1. Introduction

Diabetic cardiomyopathy (DCM) is a major cardiac complication of diabetes characterized by diastolic dysfunction and progressive systolic impairment, contributing to the high incidence of heart failure and adverse clinical outcomes in patients [1]. The pathogenesis of DCM is multifactorial and involves metabolic dysregulation, oxidative stress, and chronic inflammation [2,3]. In recent years, cellular senescence has emerged as a pivotal contributor to the advancement of DCM pathology [4,5]. This process is characterized by a spectrum of molecular changes, such as DNA damage accumulation, the induction of cell cycle inhibitors such as p16 and p21, and the secretion of a broad array of cytokines, chemokines, growth factors, and proteases, collectively known as the senescence-associated secretory phenotype (SASP) [6,7]. These alterations can be initiated not only by physiological aging but also by pathological stimuli, including redox imbalance and metabolic stress [8]. Cardiomyocytes are particularly vulnerable to senescence, with senescent cells exhibiting widespread transcriptomic reprogramming [9]. Furthermore, increased senescent cell burden within cardiac tissue has been closely linked to progressive deterioration in heart function [4,10]. The pharmacological elimination of senescent cells through senolytic compounds such as dasatinib and quercetin has demonstrated beneficial effects on cardiac structure and performance in experimental DCM models [11]. Although accumulating studies support the involvement of cellular senescence in the pathophysiology of DCM, the molecular mechanisms underlying cardiomyocyte senescence remain poorly understood.

The (pro)renin receptor (PRR) was initially identified as a component of the renin-angiotensin system (RAS), facilitating the generation of angiotensin I through its interaction with renin and prorenin, thereby contributing to blood pressure regulation and fluid balance [12]. In addition to this classical RAS-dependent role, PRR also activates angiotensin-independent pathways, including the MAPK and Wnt/β-catenin signaling pathways, which contribute to cardiovascular inflammation and fibrotic remodeling [13]. These angiotensin-independent roles of PRR are now recognized as critical contributors to the development of hypertension, adverse cardiac remodeling, and heart failure. Moreover, PRR serves as an accessory subunit of the vacuolar H⁺-ATPase (V-ATPase), playing a critical role in lysosomal acidification and intracellular pH regulation, processes essential for maintaining cellular homeostasis and cardiovascular integrity [14,15]. Recent research has increasingly linked PRR to the modulation of cellular senescence. In skeletal muscle cells, PRR has been reported to promote senescence through activation of the Wnt/YAP axis [16]. Upregulation of PRR expression has also been observed in the thoracic aorta and renal cortex of aged mice [17,18], and elevated levels of circulating soluble PRR (sPRR) have been detected in elderly individuals with heart failure [19,20]. These findings collectively point to a possible regulatory role for PRR in senescence processes; however, its involvement in cardiomyocyte senescence in DCM remains unexplored.