The non-steroidal mineralocorticoid receptor (MR) antagonist (FINERENONE) reverses Western diet-induced kidney disease by enhancing mitochondrial metabolism and decreasing lipid accumulation 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 non-steroidal MR antagonist Finerenone (FN) in a mouse model of western diet-induced obesity and insulin resistance. 10-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 finerenone (FN) for another 14 weeks (intervention studies) until they were 36 weeks old. Finerenone treatment prevented a) the increased albuminuria and kidney injury molecule 1 (KIM1), b) the expanded extracellular mesangial matrix, and podocyte injury, c) fibronectin, collagen IV, CD45 and CD68 immunostaining, d) glomerular basement membrane disruption, podocyte foot process loss, and mitochondrial structural abnormalities, e) the pro-inflammatory cytokines (MCP1), innate immunity pathways (TLR2, STING, STAT3), and fibrosis markers fibronectin, TGF{beta} and Pai1, and f) the increased kidney cholesterol levels. There was also reduced expression of nuclear receptor ERR{gamma} without changes in ERR in WD-fed mice whereas both ERR and ERR{gamma} expression levels increased after Finerenone treatment. NADH lifetime analysis showed decreased bound NADH, compatible with decreased mitochondrial 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 ERR{gamma}, and reducing lipid accumulation and inflammation.