Finerenone Reduces Renal RORγt γδ T Cells and Protects against Cardiorenal Damage

Abstract

<b><i>Introduction:</i></b> Chronic activation of the mineralocorticoid receptor (MR) leads to pathological processes like inflammation and fibrosis during cardiorenal disease. Modulation of immunological processes in the heart or kidney may serve as a mechanistic and therapeutic interface in cardiorenal pathologies. In this study, we investigated anti-inflammatory/-fibrotic and immunological effects of the selective nonsteroidal MR antagonists finerenone (FIN) in the deoxycorticosterone acetate (DOCA)-salt model. <b><i>Methods:</i></b> Male C57BL6/J mice were uninephrectomized and received a DOCA pellet implantation (2.4 mg/day) plus 0.9% NaCl in drinking water (DOCA-salt) or received a sham operation and were orally treated with FIN (10 mg/kg/day) or vehicle in a preventive study design. Five weeks after the procedure, blood pressure (BP), urinary albumin/creatinine ratio (UACR), glomerular and tubulointerstitial damage, echocardiographic cardiac function, as well as cardiac/renal inflammatory cell content by FACS analysis were assessed. <b><i>Results:</i></b> BP was significantly reduced by FIN. FACS analysis revealed a notable immune response due to DOCA-salt exposure. Especially, infiltrating renal RORγt γδ-positive T cells were upregulated, which was significantly ameliorated by FIN treatment. This was accompanied by a significant reduction of UACR in FIN-treated mice. In the heart, FIN reduced DOCA-salt-induced cardiac hypertrophy, cardiac fibrosis and led to an improvement of the global longitudinal strain. Cardiac actions of FIN were not associated with a regulation of cardiac RORγt γδ-positive T cells. <b><i>Discussion/Conclusion:</i></b> The present study shows cardiac and renal protective effects of FIN in a DOCA-salt model. The cardiorenal protection was accompanied by a reduction of renal RORγt γδ T cells. The observed actions of FIN may provide a potential mechanism of its efficacy recently observed in clinical trials.

The non-steroidal mineralocorticoid receptor antagonist finerenone and heart failure with preserved ejection fraction

“…For instance, finereone reduced the cardiac accumulation of macrophages (CD68-positive cells) in a model of cardiac dysfunction induced by short-term isoproterenol application [11]. Potent anti-fibrotic actions of finerenone in the heart were documented in the deoxycorticosterone acetate (DOCA) salt -uninephrectomy rat and mouse model, the short-term isoproterenol model, and in the Zucker fa/fa rat model [11,[73][74][75][76]. Anti-fibrotic actions of MRAs have also been recently documented in clinical studies conducted with spironolactone demonstrating a significant reduction of serum concentrations of procollagen type 1 carboxy-terminal propetide, which reflects the synthesis of type 1 collagen and correlates with histologically proven cardiac fibrosis [77].…”

“…Cardiac hypertrophy is a key criterion for HFpEF in the HFA-PEFF score [78]. Finerenone has been shown to reduce cardiac hypertrophy in different rodent models including the pressure-induced transverse aortic constriction mouse model, the DOCA salt -uninephrectomy rat and mouse model, the short-term isoproterenol model, and in the Zucker fa/fa rat model [11,73,74,76,79]. The second key diagnostic parameter for HFpEF, which is part of the HFA-PEFF and the H 2 FpEF score, is the presence of diastolic dysfunction [78,80].…”

Overview of the safety, efficiency, and potential mechanisms of finerenone for diabetic kidney diseases

“…Additionally, there is a reduction in the inflammatory population of CD11b + , F4/80 + , and Ly6C high macrophages ( 27 ). In uninephrectomized (UNX) DOCA-treated mice, the downregulation of kidney retinoid-related orphan receptor (ROR) gamma t-positive T-cells, along with a significant reduction in UACR, demonstrates significant renal protection in response to FIN treatment ( 76 ). Notably, MR antagonism by FIN can modulate inflammation as indicated by its ability to reduce proinflammatory cytokines like IL-6 and IL-1ß following renal ischemic damage ( 27 ).…”

“…Similarly, Luettges et al. ( 76 ) conducted experiments highlighting FIN’s protective effects against functional and morphological renal damage and its ability to exert antihypertensive actions in mice subjected to the DOCA-Salt model. In a rodent model transitioning from AKI to CKD, FIN demonstrated efficacy in preventing AKI induced by ischemia-reperfusion (IR) and the subsequent chronic and progressive deterioration of kidney function and structure ( 27 , 71 , 72 ).…”

Nonsteroidal Mineralocorticoid Receptor Antagonism by Finerenone—Translational Aspects and Clinical Perspectives across Multiple Organ Systems

“…Finerenone was shown to decrease the macrophage messenger RNA (mRNA) expression of proinflammatory cytokine TNF-α and M1 macrophage marker IL-1β [ 61 ]. In finerenone-treated uninephrectomized deoxycorticosterone acetate (DOCA)-treated mice, kidney retinoid-related orphan receptor (ROR) gamma t-positive T-cells were downregulated, which was accompanied by a significant reduction in the urine albumin-to-creatinine ratio (UACR), demonstrating significant renal protection [ 87 ]. In humans, IL-6 expression is induced through an MR-dependent process promoted by angiotensin II, a proinflammatory effect that can be blocked by MR antagonism [ 88 ].…”