[Show abstract][Hide abstract] ABSTRACT: High glucose levels can induce mesangial cell proliferation and extracellular matrix (ECM) accumulation through the type I activin receptor-like kinase 5 (ALK5) signaling pathway. Salt-inducible kinase 1 (SIK1) prevents fibrosis by downregulating ALK5, while the expression level of the SIK1 protein itself is downregulated by glucose in neuronal cells following ischemia. In this study, we investigated the correlation between SIK1 and the ALK5 signaling pathway in a rat glomerular mesangial cell line (HBZY-1 cells). We found that high glucose levels downregulated the expression level of SIK1 and suppressed the phosphorylation of SIK1 at Thr-182. The downregulation of SIK1 by high glucose was accompanied by the activation of the ALK5 signaling pathway, while the overexpression of SIK1 in the HBZY-1 cells resulted in a decrease in the ALK5 protein level, as well in the levels of its downstream targets, including fibronectin and plasminogen activator inhibitor type I. In conclusion, high glucose may activate the ALK5 signaling pathway by downregulating SIK1, and SIK1 may be a protective factor against cellular proliferation and ECM accumulation in glomerular mesangial cells under high glucose conditions.
Preview · Article · May 2013 · International Journal of Molecular Medicine
[Show abstract][Hide abstract] ABSTRACT: Forkhead box O1 (FOXO1) plays an important role in glucose metabolism at the gene transcription level. Increased FOXO1 activity results in hyperglycemia by promoting the expression of gluconeogenic enzymes such as phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase), and inhibiting glucokinase (GK). This study evaluates the effect of Zhenqing Recipe (ZQR), a Chinese herbal medicine, on hyperglycemia and its molecular mechanisms. Type 2 diabetic rats, developed by high-fat diet combined with low-dose STZ injections, were randomly divided into untreated diabetic, ZQR and metformin group. Normal rats served as control. After an eight-week treatment, fasting blood glucose was significantly decreased and insulin sensitivity index was obviously increased in the ZQR group. ZQR also improved the oral glucose tolerance. Compared with the control group, the mRNA levels of PEPCK and G6Pase were significantly elevated, while GK mRNA expression was decreased in the liver of untreated diabetic rats. ZQR significantly reduced the mRNA levels of PEPCK and G6Pase, and increased GK mRNA expression. The hepatic mRNA and protein expression of FOXO1 in the untreated diabetic group was markedly increased compared to controls. The administration of ZQR significantly decreased the mRNA and protein levels of hepatic FOXO1. The data suggest that ZQR improves glucose metabolism and insulin sensitivity, which is accompanied with regulating mRNA expression of GK and gluconeogenic genes. This anti-diabetic effect of ZQR is due to its ability to repress hepatic FOXO1 at the mRNA and protein level.
No preview · Article · Jul 2012 · The American Journal of Chinese Medicine
[Show abstract][Hide abstract] ABSTRACT: Zhenqing Recipe (ZQR), a Chinese herbal prescription, is used to improve renal function of patients with diabetic nephropathy. In current research, the therapeutic effects of ZQR on type 2 diabetic nephropathy and the underlying molecular mechanisms were explored.
Animal model with diabetic nephropathy was developed by high fat/sucrose diet feeding plus streptozotocin injection for 4 weeks. The diabetic rats were then orally administered with ZQR extract at the dose of 4 g/kg, 8 g/kg body weight/day for 8 weeks.
Serum glucose, triglyceride and total cholesterol in untreated diabetic rats were significantly higher than that of normal control rats. ZQR treatment not only reduced serum glucose level in diabetic rats, but also decreased serum triglyceride and total cholesterol in a dose-dependent manner. Urinary albumin excretion rate, serum urea and creatinine were significantly decreased in ZQR groups compared with untreated diabetic group. Histopathological study of kidney samples showed that extracellular mesangial matrix expansion in diabetic rats was suppressed by ZQR treatment. Both mRNA and protein levels of sterol regulatory element binding-protein-1c (SREBP-1c), and its target genes including acetyl-CoA carboxylase (ACC) and fatty acid synthase (FAS) in renal cortex were significantly decreased in ZQR treated rats compared to untreated diabetic rats. Consequently, renal triglyceride was significantly reduced in ZQR groups. Furthermore, ZQR significantly inhibited the overexpression of transforming growth factor-β1 and fibronectin in the renal cortex of diabetic rats.
Oral treatment of ZQR improved diabetic nephropathy by inhibiting the overexpression of SREBP-1c and its target genes including ACC and FAS in experimental type 2 diabetic rats.
No preview · Article · May 2012 · Journal of ethnopharmacology