Activation of the TGF-β1/HIPK2 signaling pathway exacerbates EMT injury in renal tubular epithelial cells in diabetic kidney disease.

Diabetic kidney disease (DKD) is a common and challenging microvascular complication of diabetes. TGF-β1-mediated epithelial-to-mesenchymal transition (EMT) in renal tubular epithelial cells, characterized by loss of epithelial polarity and intercellular adhesion alongside acquisition of a mesenchymal phenotype, is widely recognized as a key driver of DKD. Here, we reveal that renal interstitial fibrosis (RIF) and EMT constitute important pathological foundations for DKD progression, validated in both clinical DKD patients and DKD mouse models. Concurrently, we confirm the elevated expression of homoeotic domain-interacting protein kinase 2 (HIPK2) in DKD, though its regulatory role in EMT remains unclear. We further established a DKD-EMT cellular model by inducing human renal tubular epithelial cells (HK-2) with TGF-β1 combined with high glucose stimulation. Here, we found that inhibiting HIPK2 expression significantly delayed EMT progression and improved RIF in DKD. Thus, our study provides a novel therapeutic strategy for DKD progression and demonstrates that HIPK2 serves as a potential therapeutic target for DKD-EMT.