Upregulation of BNIP3 alleviates renal tubular cell injury by activating mitophagy in diabetic nephropathy

Oct 21, 2025Biochemical pharmacology

Increasing BNIP3 reduces kidney tubule cell damage by triggering removal of damaged mitochondria in diabetic kidney disease

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Abstract

Bcl-2-interacting protein 3 (BNIP3) expression is reduced in renal tubular cells from patients with diabetic nephropathy (DN) and correlates significantly with urinary albumin-to-creatinine ratio.

Reduced BNIP3 expression is linked to the progression of diabetic nephropathy.
Overexpression of BNIP3 in experimental models decreased kidney injury markers and improved mitophagy function.
Bioinformatics analysis suggests a strong correlation between BNIP3 and the transcription factor STAT3.
High glucose conditions increase STAT3 binding to the BNIP3 promoter, leading to altered BNIP3 expression levels.
BNIP3 may serve as a potential biomarker for diabetic nephropathy prevention and treatment.

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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.

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Upregulation of BNIP3 alleviates renal tubular cell injury by activating mitophagy in diabetic nephropathy

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