Sodium-glucose cotransporter 2 inhibitors alleviate renal fibrosis in diabetic kidney disease by inhibiting Hmgcs2 and Btg2 in proximal tubular cells

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have been shown to ameliorate renal fibrosis in diabetic kidney disease (DKD), but the mechanism has not been fully explored. The single-cell sequencing (scRNA-seq) data were downloaded from the Gene Expression Omnibus (GEO) database, and we selected the tissue data from db/m mice, db/db mice and db/db mice with SGLT2i treatment. The results were also validated by immunofluorescent staining and western blot in vivo and in vitro, respectively. Our study demonstrates that SGLT2i directly ameliorated fibrosis of proximal tubular cells by downregulating 3-hydroxy-3-methylglutaryl-CoA synthase 2 (Hmgcs2) expression in S1 proximal tubular segment cells (PT_S1) and decreasing the number of proximal tubular cell cluster with B-cell translocation gene 2 (Btg2) highly expressed (Btg2_PT). In addition, SGLT2i could indirectly influence macrophages through cell-cell communication between epithelial cells and macrophages, specifically via the App-CD74 ligand-receptor pair, thus suppressing the inflammatory response in macrophages, ultimately contributing to the delay in DKD progression. Our study found that Hmgcs2 and Btg2 are therapeutic targets for Sodium-glucose cotransporter 2 inhibitors to ameliorate kidney fibrosis in diabetic kidney disease. Single-cell sequencing technology provided a high resolution of this study at the cellular level.