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

CONTEXT: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12967-025-06788-6.