The nonsteroidal MR antagonist finerenone reverses Western diet-induced kidney disease by regulating mitochondrial and lipid metabolism and inflammation.

Mineralocorticoid receptor (MR) overactivation plays a crucial role in the pathogenesis of chronic kidney disease, as well as several cardiovascular and arterial diseases. Current studies determined the mechanisms of the beneficial kidney effects of the nonsteroidal MR antagonist finerenone (FN) in a mouse model of Western diet-induced obesity and insulin resistance. Ten-week-old male C57BL/6J mice were fed a low-fat (LF) or a Western diet (WD) for 12 weeks followed by treatment with either vehicle or FN for another 14 weeks (intervention studies) until they were 36 weeks old. Finerenone treatment prevented 1) the increased albuminuria and kidney injury molecule 1 (KIM1); 2) the expanded extracellular mesangial matrix and synaptopodin coverage; 3) fibronectin, collagen IV, CD45, and CD68 immunostaining; 4) glomerular basement membrane disruption, podocyte foot processes effacement, and mitochondrial structural abnormalities; 5) the proinflammatory cytokines [monocyte chemoattractant protein-1 (MCP-1)], innate immunity pathways [Toll-like receptor-2 (TLR2), stimulator of interferon genes (STING), signal transducer and activator of transcription 3 (STAT3)], and fibrosis markers fibronectin, transforming growth factor-β (TGFβ), and plasminogen activator inhibitor-1 (Pail); and 6) the increased kidney cholesterol levels. There was also reduced expression of nuclear receptor estrogen-related receptor-γ (ERRγ) without changes in ERRα in WD-fed mice, whereas both ERRα and ERRγ expression levels increased after finerenone treatment. NADH lifetime analysis showed decreased bound NADH, compatible with decreased mitochondrial oxidative phosphorylation (OXPHOS) in the kidneys of WD-fed mice compared to controls, which was prevented by finerenone treatment. In conclusion, finerenone treatment exhibits a renal protective role and prevents the progression of kidney disease by regulating mitochondrial function, most likely via ERRγ, and reducing lipid accumulation and inflammation. NEW & NOTEWORTHY Finerenone, a nonsteroidal mineralocorticoid receptor (MR) antagonist, has shown promise in protecting against kidney damage in obese, insulin-resistant mice. It effectively prevents albuminuria, inflammation, fibrosis, and mitochondrial dysfunction, while also restoring estrogen-related receptor-γ (ERRγ) expression. These results suggest that finerenone could play a key role in halting the progression of kidney disease by enhancing mitochondrial function and reducing harmful lipid accumulation, offering a potential therapeutic strategy for managing kidney complications in metabolic disorders.