MR antagonist (FINERENONE) reverses western diet induced kidney disease by enhancing mitochondrial metabolism and decreasing lipid accumulation and inflammation

Background: Mineralocorticoid receptor (MR) overactivation plays a crucial role in the pathogenesis of chronic kidney disease, as well as several cardiovascular and arterial diseases. Clinical studies have demonstrated the beneficial effects of MR antagonists (MRAs) on kidney disease. The current studies tested the mechanisms of the beneficial effects of the non-steroidal MR antagonist Finerenone (FN) in a mouse model of diet induced obesity and insulin resistance. Methods: 2-month-old C57BL/6J mice were fed low fat (LF) or western diet (WD) for 3 months followed by vehicle or FINERENONE (FN) for another 3-months ( intervention studies ) until they were 8-months old. At the end of the study, 24-hour urine was collected, and serum and kidneys were harvested for biochemistry. Plasma and tissue levels of triglycerides (TG) and total cholesterol (TC) concentration were determined. Periodic acid-Schiff (PAS) and picrosirius red (PSR) staining were performed to determine the glomerular mesangial expansion and interstitial fibrosis. Two-photon fluorescence lifetime imaging microscopy (FLIM) was performed and analyzed for free/bound NADH ratios, indicating the relative amount of glycolysis versus OXPHOS. Immunofluorescence microscopy was performed for synaptopodin, fibronectin, collagen IV, CD45 and CD68, as a differentiated podocyte, glomerular injury marker and infiltrated inflammatory response. Transmission electron microscopy (TEM) was performed to assess the glomerular ultrastructure, podocyte foot processes, and mitochondrial morphology. Results: The WD fed mice exhibited significantly increased albuminuria and kidney injury molecule 1 (KIM1) compared LF fed mice, which was decreased with Finerenone (FN) treatment. PAS, PSR and synaptopodin positive staining shows the expanded extracellular mesangial matrix, podocyte loss and renal fibrosis in kidney of WD fed mice, which were prevented with FN. In WD fed kidneys, immunostaining shows accumulation of fibronectin, collagen IV together with infiltrated CD45 and CD68 positive signals and FN treatment prevented these changes. WD-fed mice kidneys had increased gene expression of pro-inflammatory cytokines (MCP1, TGFβ), innate immunity pathways (TLR2, STING, STAT3), and fibrosis marker fibronectin and Pai1, and their expression were reduced by Finerenone. Kidney cholesterol levels were elevated in WD-fed mice and reduced by Finerenone. Interestingly, westernblot results showed reduced expression of nuclear receptors ERRγ without changes in ERRα in WD-fed mice whereas both ERRα and ERRγ expression levels increased markedly with FN. NADH lifetime analysis showed decreased mitochondrial OXPHOS in kidneys of WD fed mice compared to controls, whereas this change was prevented by FN treatment. Electron microscopy revealed glomerular basement membrane disruption, podocyte foot process loss, and mitochondrial structural abnormalities in WD-fed kidneys, which were improved by Finerenone. Conclusion: Finerenone treatment exhibits a renal protective role and prevents the progression of kidney disease by regulating mitochondrial function via ERRγ and reducing lipid accumulation, leading to prevention of an inflammatory response in a mouse model of western diet induced obesity and insulin resistance. This work was supported by NIH (NIDDK) award numbers R01-DK127830 (ML), R01 DK139676 (ML) This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.