Hypoxia-inducible factor-1α promotes epithelial-to-mesenchymal transition through upregulating cathepsin S expression...

Tubulointerstitial fibrosis (TIF) plays an important role in the deterioration of diabetic kidney disease (DKD). Epithelial-to-mesenchymal transition (EMT) in tubular epithelial cells (TECs) leads to TIF in the progression of DKD. Hypoxia-inducible factor-1α (HIF-1α; HIF1A) has been elucidated to promote EMT and TIF through inducing transforming growth factor-β1 (TGF-β1) pathway. In this study, we aimed to explore the mediation effect of key genes in HIF‑1α‑induced EMT and TIF in DKD. Tubulointerstitial gene expression profiling data from DKD patients and healthy controls (HCs) were acquired from the GEO database, R packages were used for bioinformatics analysis, and the db/db mice and proximal TEC line (HK-2) were used to validate the bioinformatic findings. Consequently, we focused on cathepsin S (CTSS). Functional enrichment indicated that HIF1A and CTSS were jointly involved in inflammatory activation, extracellular matrix deposition, and cellular interaction. In vitro and in vivo experiments validated that in DKD models, HIF‑1α could upregulate Cathepsin S to promote partial EMT-associated phenotypic shift and fibrotic remodeling in TECs, thereby deteriorating diabetic kidney injury. Conclusively, CTSS may serve as a downstream effector of HIF‑1α participating in the regulation of partial EMT-associated phenotypic shift and fibrotic remodeling of TECs in diabetic kidney disease models.