Upregulation of BNIP3 Alleviates Renal Tubular Cell Injury by Activating Mitophagy in Diabetic Nephropathy

Aims: 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. It is crucial to study new therapeutic targets and gain a deeper understanding of the molecular mechanisms underlying DN.Results: BNIP3 expression is reduced in renal tubular cells from both renal biopsies of patients with DN and db/db mice, 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, reactive oxygen species production 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 STAT3 showing the strongest positive correlation. Knockdown of STAT3 in high glucose-stimulated MTECs resulted in increased BNIP3 expression. ChIP assays further revealed that high glucose enhanced STAT3 binding to the BNIP3 promoter.