Diabetic nephropathy (DN) leads to significant renal tubular and interstitial damage, yet effective preventive and therapeutic strategies remain scarce. Abnormal mitophagy may contribute to DN progression, but the underlying regulatory mechanisms are poorly understood. Bcl-2-interacting protein 3 (BNIP3) expression is reduced in renal tubular cells from both renal biopsies of patients with DN, correlating significantly with urinary albumin-to-creatinine ratio (UACR) and various clinicopathological markers in patients with DN. Gain-of-function experiments in vitro and in vivo confirmed its role in DN pathogenesis. Overexpression of BNIP3 mitigated kidney injury molecule-1 (KIM-1) levels and restored mitophagy function in db/db mice and high glucose-treated renal tubular cells. Bioinformatics analysis identified a high probability of transcription factor binding sites within the BNIP3 sequence, with signal transducer and activator of transcription 3 (STAT3) showing the strongest positive correlation. Knockdown of STAT3 in high glucose (HG)-stimulated mouse renal tubular epithelial cells (MTECs) resulted in increased BNIP3 expression. ChIP assays further revealed that high glucose enhanced STAT3 binding to the BNIP3 promoter. In conclusion, this study demonstrates that BNIP3 expression correlates with the clinical progression of DN, and its overexpression mitigates renal tubular injury by restoring mitophagy. Thus, BNIP3 presents a potential biomarker for the prevention and treatment of DN.
