The Transfer of USP25 by Exosomes of Adipose Tissue‐Derived Mesenchymal Stem Cells Ameliorates Diabetic Nephropathy Through Stabilizing SMAD7 Expression

ABSTRACT Adipose tissue‐derived mesenchymal stem cells (ADSCs) are identified to be potential therapeutic candidates for diabetic nephropathy (DN) through secreting exosomes (Exos). Ubiquitin‐specific protease 25 (USP25) has been reported to be involved in DN‐induced renal injury. Herein, this study aimed to investigate whether ADSCs affected DN progression by Exo transfer of USP25. High glucose (HG)‐induced mouse podocytes were used to mimic DN‐induced injury for in vitro viability, inflammation, and apoptosis analyses. The db/db mice of DN were established for renal injury and function analysis in vivo. The deubiquitination effect of USP25 was analyzed by cellular ubiquitination and immunoprecipitation assays. ADSCs reversed HG‐induced apoptosis and inflammation in podocytes, and these effects were achieved by Exo‐mediated transfer of USP25. Mechanistically, USP25 interacted with SMAD7 protein and elevated its expression in podocytes via inducing SMAD7 deubiquitination. USP25 transferred via ADSC‐Exos abolished HG‐induced apoptosis and inflammation in podocytes by elevating SMAD7 protein levels. In vivo assay also confirmed that ADSC‐Exo attenuated Type 2 Diabetes Mellitus‐induced kidney injury and podocyte apoptosis and inflammation by releasing USP25. ADSCs attenuated T2DM‐induced kidney injury, podocyte apoptosis, and inflammation via elevating SMAD7 stabilization through exosome transfer of USP25.