Effects of Nonsteroidal Mineralocorticoid Antagonist (Finerenone) in Western Diet-Induced Kidney Diseases

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Background: Mineralocorticoid receptor (MR) overactivation plays a crucial role in the pathogenesis of chronic kidney disease, several cardiovascular and arterial diseases. Recently the non-steroidal MR antagonist Finerenone (FN) was shown to have highly beneficial cardiac and renal protective effects. The purpose of these studies was to determine the mechanisms of the beneficial effects FN in kidney disease in a mouse model of western diet induced obesity and insulin resistance. Methods: 2-month old C57BL/6J mice fed on low fat (LF) or western diet (WD) were treated with vehicle or FN for 6-months (prevention studies) or after 3 months on the LF or WD at 5 months of age, mice treated with vehicle or FN for 3 months (intervention studies) until they were 8 months old. Results: Mice fed a Western diet (WD) had increased body weight and kidney weight, whereas Finerenone reduced kidney weight ratio without affecting body weight and blood glucose levels remained unchanged. WD-fed mice had higher plasma levels of TG and TC, reduced by FN. The WD fed mice exhibited significantly increased albuminuria and KIM1 which was decreased with FN. Kidneys of WD-fed mice showed increased expression levels of pro-inflammatory cytokines (MCP1, TGFβ), innate immunity pathways (TLR2, STING, STAT3), and fibrosis marker fibronectin and PAI-1, which were significantly reduced by FN. Interestingly, kidney cholesterol and ceramide levels were markedly increased in WD fed mice, which were reduced by FN. Electron microscopy revealed glomerular basement membrane disruption, podocyte foot process loss, and mitochondrial structural abnormalities in WD-fed mice, all improved by FN. Conclusions: Our data shows that administration of Finerenone exhibits a renal protective role and prevents the progression of kidney disease in a mouse model of western diet induced obesity and insulin resistance. Funding: Commercial Support - Bayer

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