Finerenone reduces renal RORgt gd T-Cells and protects against cardiorenal damage

Abstract

Abstract Chronic activation of the mineralocorticoid receptor (MR) through the agonist aldosterone leads to pathological processes like inflammation, fibrosis, and increased blood pressure. Therefore, MR antagonists (MRA) belong to guideline-based therapy for hypertension and heart failure with reduced ejection fraction. The nonsteroidal, selective MRA finerenone (FIN) induces distinct pharmacological actions when compared to steroidal MRAs including less adverse effects and improved efficacy (e.g. anti-fibrosis). In this study, we investigated the effects of FIN in a deoxycorticosterone acetate (DOCA)-salt model which induces an increase of blood pressure and end organ damage including hypertrophy, fibrosis, and inflammatory cell infiltration in heart and kidney. Male C57BL6/J mice were either uni-nephrectomized in addition to DOCA-pellet application (2.4mg/d) and 0.9% NaCl in the drinking water (DOCA/UNX) or received a sham operation. One week prior to the surgery, oral treatment with FIN (10mg/kg/d) or vehicle (VEH) started and lasted throughout the experiment. Five weeks after the procedure, final examinations including blood pressure (BP) measurement, urine analysis, speckle-tracking echocardiography (STE), and FACS analysis of the heart and kidney were performed. BP was significantly reduced by FIN treatment. FACS analysis revealed a notable immune response due to DOCA/ UNX exposure. Especially infiltrating renal RORγt γδ T-Cells were upregulated, which was significantly ameliorated by the FIN-treatment. This was accompanied by an improvement of kidney function shown by a reduction of the urinary albumin/creatinine ratio in FIN-treated mice. In the heart, FIN reduced DOCA/ UNX-induced cardiac hypertrophy, cardiac fibrosis and led to an improvement of the global longitudinal strain (GLS) in the STE-analysis. Cardiac actions of FIN were not associated with a regulation of cardiac RORγt γδ T-Cells. The present study shows cardiac and renal protective effects of FIN in a DOCA/UNX model. The cardiorenal protection was accompanied by a reduction of renal RORγt γδ T-Cells. Anti-inflammatory actions of FIN may provide a potential mechanism of its clinical efficacy recently observed in clinical trials. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Bayer AG