%0 Journal Article
%T Both ERK/MAPK and TGF-Beta/Smad Signaling Pathways Play a Role in the Kidney Fibrosis of Diabetic Mice Accelerated by Blood Glucose Fluctuation
%A Xiaoyun Cheng
%A Wenke Gao
%A Yongyan Dang
%A Xia Liu
%A Yujuan Li
%A Xu Peng
%A Xiyun Ye
%J Journal of Diabetes Research
%D 2013
%I Hindawi Publishing Corporation
%R 10.1155/2013/463740
%X Background. The notion that diabetic nephropathy is the leading cause of renal fibrosis prompted us to investigate the effects of blood glucose fluctuation (BGF) under high glucose condition on kidney in the mice. Methods. The diabetic and BGF animal models were established in this study. Immunohistochemistry, Western blot, and RT-PCR analysis were applied to detect the expression of type I collagen, matrix metalloproteinase-1 (MMP1), metalloproteinase inhibitor 1 (TIMP1), transforming growth factor beta 1 (TGF-¦Â1), phosphorylated-ERK, p38, smad2/3, and Akt. Results. BGF treatment increased type I collagen synthesis by two times compared with the control. The expression of MMP1 was reduced markedly while TIMP1 synthesis was enhanced after BGF treatment. ERK phosphorylation exhibits a significant increase in the mice treated with BGF. Furthermore, BGF can markedly upregulate TGF-¦Â1 expression. The p-smad2 showed 2-fold increases compared with the only diabetic mice. However, p-AKT levels were unchanged after BGF treatment. Conclusions. These data demonstrate that BGF can accelerate the trend of kidney fibrosis in diabetic mice by increasing collagen production and inhibiting collagen degradation. Both ERK/MAPK and TGF-¦Â/smad signaling pathways seem to play a role in the development of kidney fibrosis accelerated by blood glucose fluctuation. 1. Introduction Diabetes can cause a wide range of health complications such as atherosclerosis, cardiac dysfunction, retinopathy, and nephropathy. Hyperglycemia is a major sign of diabetes mellitus (DM) and the main cause for its various complications. The side effects of hyperglycemia can be categorized into two types, persistent elevation of blood glucose (BG) levels and blood glucose fluctuation (BGF) [1], which are closely correlated with the DM prognosis, pathogenesis, and complications. Larger BGF is associated with a higher incidence of chronic diabetic complications and a poorer prognosis [2]. Clinical studies have shown that the risks associated with long-term BGF were much more detrimental than that of chronic elevation of BG levels [3]. Furthermore, there are some evidences that intermittent fluctuation of high glucose can induce lesions of varying degrees in glomerular mesangial and vascular endothelial cells in vitro [4¨C6]. Thus, the effects of BGF on diabetic complications need to be determined. Diabetic nephropathy (DN) is the leading cause of renal fibrosis and chronic renal failure [7]. Renal fibrosis was characterized by glomerulosclerosis and tubulointerstitial fibrosis, which would reduce
%U http://www.hindawi.com/journals/jdr/2013/463740/