Abstract
Senescence of renal tubular epithelial cells plays an important role in diabetic nephropathy, but the mechanism is unknown. Metformin may alleviate diabetic nephropathy by reducing this senescence. This study is aimed at clarifying the effects and mechanism of metformin on the senescence of renal tubular epithelial cells in diabetic nephropathy. We found that metformin reduced the expression of senescence-associated gene P21 in high-glucose-induced (30 mmol/L) renal tubular epithelial cells and decreased the β-galactosidase positive staining rate (decreased 16%, p < 0.01). Metformin was able to reduce senescence by upregulating the expression of RNA-binding protein MBNL1 and miR-130a-3p and reducing STAT3 expression. MBNL1 prolonged the half-life of miR-130a-3p, and miR-130a-3p could negatively regulate STAT3 by binding to its mRNA 3′UTR. In db/db diabetic mice, we found an enhanced senescence level combined with low expression of MBNL1 and miR-130a-3p and high expression of STAT3 compared with db/m control mice during nephropathy development. Meanwhile, metformin (200 mg/kg/day) could increase the expression of MBNL1 and miR-130a-3p and decreased STAT3 expression, thus reducing this senescence in db/db mice. Our results suggest that metformin reduces the senescence of renal tubular epithelial cells in diabetic nephropathy via the MBNL1/miR-130a-3p/STAT3 pathway, which provided new ideas for the therapy of this disease.
Highlights
Diabetes is a metabolic disorder characterized by elevated blood glucose levels [1]
Our results suggest that metformin reduces the senescence of renal tubular epithelial cells in diabetic nephropathy via the MBNL1/miR-130a-3p/STAT3 pathway, which provided new ideas for the therapy of this disease
Studies have revealed that renal tubular epithelial cells present premature senescence in type II diabetic nephropathy, indicating that senescence of renal tubular epithelial cells is one of the mechanisms involved in the progression of diabetic nephropathy [5]
Summary
The increasing morbidity of diabetes exposes more patients to diabetic complications, e.g., diabetic nephropathy [2], which is the major contributor to end-stage renal disease (ESRD) and involves renal glomerular, vascular, and tubular injuries [3, 4]. Studies have revealed that renal tubular epithelial cells present premature senescence in type II diabetic nephropathy, indicating that senescence of renal tubular epithelial cells is one of the mechanisms involved in the progression of diabetic nephropathy [5]. The occurrence and development of various diseases can trigger cell senescence, and the aged cells can drive and accelerate disease progression [6]. The high-glucose-induced accelerated senescence of renal tubular epithelial cells is an important cellular event that precedes renal interstitial injury in diabetic nephropathy [8]
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