Abstract
Renal interstitial fibrosis is considered to be the typical manifestation of diabetic nephropathy (DN). Mangiferin has shown positive effect on the prevention or treatment of diabetes and its complications. The aim of this study was to explore the inhibitive effect and mechanism of mangiferin on renal interstitial fibrosis in diabetic mice. Streptozotocin- (STZ-) induced diabetic mice were treated with mangiferin (15, 30, and 60 mg/kg/d) for 4 weeks. The morphology of kidneys was observed by Masson's trichrome staining, and the biochemical parameters (fasting blood glucose (FBG), triglyceride (TG), total cholesterol (TC), blood urea nitrogen (BUN), serum creatinine (SCr), and urine protein) were determined by kits. In addition, the levels of inflammatory cytokines (tumor necrosis factor-α (TNF-α), interleukin- (IL-) 6, and IL-1β), antioxidant enzymes (SOD, CAT, and GSH-Px), MDA, and ROS were assessed. Furthermore, the expressions of fibronectin (FN), collagen I (Col I), and α-SMA were measured by immunohistochemistry. Regulations of TGF-β1 and the PTEN/PI3K/Akt pathway were detected by Western blotting. Treatment with mangiferin significantly ameliorated renal dysfunction in diabetic mice, as evidenced by the increase in body weight and decreases in FBG, TG, TC, BUN, SCr, urine protein, and the kidney to body weight ratio (KW/BW). Furthermore, mangiferin treatment prevented renal interstitial fibrosis evidenced by decreases in the positive expression of FN, Col I, and α-SMA, in comparison with morphological changes in the renal tissue. Meanwhile, mangiferin increased antioxidant enzymes, reduced the TNF-α, IL-6, and IL-1β, as well as MDA and ROS. Additionally, mangiferin administration also downregulated TGF-β1, upregulated PTEN, and decreased the phosphorylation of both PI3K and Akt. These findings demonstrate that mangiferin may reduce inflammation and oxidative stress in DN, thereby inhibiting the renal interstitial fibrosis by reducing the TGF-β1-mediated elevation of Col I, FN, and α-SMA through the PTEN/PI3K/Akt pathway.
Highlights
Diabetes is a kind of metabolic disease characterized by chronic elevated blood glucose levels
The body weights were increased in a dose-dependent manner compared with the model mice (P < 0:05, Figure 1(c))
phosphoinositide 3-kinase (PI3K) and p-Akt/Akt expressions and simultaneously increased PTEN proteins in the BpV-treated diabetic mice (P < 0:05). These findings demonstrate that mangiferin increases resistance to renal interstitial fibrosis by modulating the PTEN/PI3K/Akt signaling pathway, which can serve as a noninvasive biomarker and as a pathologic mediator and therapeutic target of kidney fibrosis
Summary
Diabetes is a kind of metabolic disease characterized by chronic elevated blood glucose levels. Long-term chronic hyperglycemia induces disorders of fat and protein metabolism, which causes a series of complications in retinal, kidney, and nerve systems [2,3,4]. Diabetic nephropathy (DN) is the most serious complication of diabetes It is characterized by the loss of renal cells and their replacement by extracellular matrix (ECM), eventually leading to glomerulosclerosis and tubulointerstitial fibrosis [5]. Oxidative stress and chronic inflammation play crucial roles in the development of DN [6, 7]. Hyperglycemia increases the generation of reactive oxygen species (ROS), Journal of Diabetes Research which activate signal transduction and induce the increases of fibrotic factors, such as fibronectin (FN), α-smooth muscle actin (α-SMA), and collagen I [3, 8]. It is necessary and urgent to find natural, effective, and safe drugs to treat DN
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