Microbiota-Derived Corisin Accelerates Kidney Fibrosis by Promoting Cellular Aging

The increasing global prevalence of diabetic nephropathy poses substantial health and economic burdens. Currently, effective anti-fibrotic therapies for managing kidney fibrosis associated with chronic kidney disease are lacking. This study reveals corisin, a microbiota- derived peptide, as a central driver in the progression of diabetic kidney fibrosis. Corisin levels were found to be markedly elevated in the serum and urine of diabetic chronic kidney disease patients relative to healthy controls, with strong correlations to advanced disease stages and declining renal function. In a murine model of kidney fibrosis, corisin levels were similarly heightened, directly contributing to acute kidney injury and worsening fibrosis and renal impairment. Notably, the use of a monoclonal anti-corisin antibody significantly reduced nephropathy severity in diabetic mice. Through molecular dynamics simulations and experimental validation, we demonstrated that corisin interacts with human serum albumin, potentially enhancing its renal accumulation and pathological impact. The pathogenic mechanism of corisin involves the acceleration of cellular senescence and the induction of epithelial-mesenchymal transition and apoptosis in kidney cells. These findings underscore the critical role of corisin in diabetic nephropathy and suggest a promising new target for therapeutic intervention. We wish to acknowledge gracious support for this work from a generous gift from the Charles and Margaret Levin Foundation, and grants (as noted in the submission) from both the Japan Society for the Promotion of Science and the Japan Science and Technology Agency.