Mangiferin Alleviates Renal Interstitial Fibrosis in Streptozotocin-Induced Diabetic Mice through Regulating the PTEN/PI3K/Akt Signaling Pathway

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.

MiR-25-3p targets PTEN to regulate the migration, invasion, and apoptosis of esophageal cancer cells via the PI3K/AKT pathway

“…Similarly, in the present study, we found that PTEN not only inhibited the migration and invasion, and induced apoptosis of EC cells, but also reversed the effect of miR-25-3p on EC cells, which further confirmed that miR-25-3p regulated the migration, invasion, and apoptosis of EC cells by targeting PTEN. It's also well known that the activity of PTEN antagonizes the PI3K/AKT pathway to suppress cancer cell survival, which means that deficient PTEN expression leads to the PI3K/AKT pathway activation, thereby enhancing cell anti-apoptosis [33][34][35]. In investigating the down-stream mechanism of miR-25-3p mediated in EC in the present study, we also observed that enhanced PTEN expression suppressed the activation of the PI3K/AKT pathway, and miR-25-3p-induced decrease of PTEN expression further enhanced the PI3K/AKT pathway activation, while overexpression of PTEN could inhibit the effect of miR-25-3p on this pathway.…”

Pathogenic Pathways and Therapeutic Approaches Targeting Inflammation in Diabetic Nephropathy

“…Inhibition of this pathway with rapamycin decreases macrophage infiltration and CCL2 release [239]. Furthermore, in a mouse model of diabetes, the treatment with mangiferin reduced IL-6, TNF-α, and Il-1β expression by inhibiting PTEN/PI3K/Akt pathway [240].…”

<p>Study on the Risk Factors for Hyperuricaemia and Related Vascular Complications in Patients with Type 2 Diabetes Mellitus</p>

“…45 TG and TC were both independent risk factors for DN. 46,47 A network Mendelian randomization study showed a positive correlation between TG and CHD. 48…”