Human Umbilical Cord Mesenchymal Stem Cells Reduce Renal Tubular Epithelial Cell Apoptosis by Regulating the Wnt/β‐Catenin Pathway in Diabetic Nephropathy

ABSTRACT Diabetic nephropathy (DN), a leading cause of kidney failure, involves early renal tubular epithelial cell (TEC) apoptosis. This study investigated whether human umbilical cord‐derived mesenchymal stem cells (hUCMSCs) protect against DN‐related TEC apoptosis by modulating the Wnt/β‐catenin signaling pathway. A Type 2 diabetic rat model was established using a high‐fat diet and streptozotocin injection. hUCMSCs were administered intravenously. In vitro, HK11 cells were treated with high glucose and palmitate (HG/P), with or without hUCMSCs and the Wnt/β‐catenin agonist SKL2001. Apoptosis, mitochondrial function, and oxidative stress were assessed by Annexin V‐FITC/PI, JC‐1, ROS staining, and Western blotting. Pathway activation was evaluated by immunoblotting, immunohistochemistry, and immunofluorescence. hUCMSCs alleviated renal tubular injury and reduced TEC apoptosis in diabetic rats. In vitro, hUCMSCs mitigated HG/P‐induced ROS accumulation, mitochondrial dysfunction, and apoptosis, accompanied by upregulation of Bcl‐2 and downregulation of Bax and cleaved caspase‐3. Mechanistically, hUCMSCs suppressed HG/P‐induced activation of Wnt/β‐catenin signaling, as evidenced by decreased β‐catenin nuclear accumulation and reduced Wnt5a expression, together with restoration of p‐GSK3β levels. Co‐treatment with the Wnt/β‐catenin agonist SKL2001 reversed these molecular changes and partially attenuated the anti‐apoptotic effects of hUCMSCs. hUCMSCs protect TECs from HG/P‐induced apoptosis by inhibiting the Wnt/β‐catenin pathway.