Finerenone improves ventricular remodeling and cardiac function in hypertensive rats via IRE1 modulation of XBP1 and TRAF2

BACKGROUND: Finerenone, a novel nonsteroidal mineralocorticoid receptor (MR) antagonist, has shown antihypertensive activity and improved cardiac function in clinical studies, but the role and target of finerenone in the prevention and treatment of ventricular remodeling in hypertension remains unclear. In the present study, hypertensive rats were employed to evaluate the beneficial effects of finerenone on ventricular remodeling and cardiac function in hypertension and to identify the related targets. METHOD: Hypertensive two-kidney, one-clip (2K1C) Sprague-Dawley rats were randomly divided into three groups: sham-operated, 2K1C model, and finerenone-treated groups (2 mg/kg/day, Bayer Pharmaceuticals, HJ20220057). All groups were treated for 8 weeks. Blood pressure, echocardiographic measurements, biochemical parameters related to cardiovascular remodeling and endoplasmic reticulum (ER) stress markers were evaluated. Cultured H9C2 cells were used to determine the effect of finerenone on cardiomyocytes administered Ang-II. RESULT: Compared with the model group, finerenone significantly reduced SBP, DBP, cardiac index, left ventricular mass index, NT-proBNP, and sST2 levels. Left ventricular remodeling and cardiac function were significantly improved after treatment with finerenone for 8 weeks. Finerenone effectively decreased the protein expression of the ER stress marker GRP78 and reduced the protein levels of p-IRE1, XBP1, and TRAF2 in myocardial tissue samples from hypertensive rats, thus decreasing ER stress in the myocardial tissue, as well as the production of the inflammatory factors IL-6 and TNF-α. In addition, finerenone significantly decreased apoptosis in H9C2 cells induced by Ang-II. Furthermore, the modulatory effects of finerenone on ER stress factors in cardiomyocytes were identified. CONCLUSION: Finerenone effectively lowers blood pressure and improves ventricular remodeling and cardiac function in hypertensive rats. These effects may be mediated via IRE1-dependent regulation of XBP1 and TRAF2, leading to reduced ER stress, inflammation, and cardiomyocyte apoptosis. Comparisons among the sham, model, and treatment groups confirm the cardioprotective role of finerenone in hypertensive heart disease.