Effects of berberine on matrix accumulation and NF-kappa B signal pathway in alloxan-induced diabetic mice with renal injury.
ABSTRACT One of the main pathological changes in diabetic nephropathy is the renal fibrosis, which includes glomerulosclerosis and tubulointerstitial fibrosis. In vivo and in vitro studies demonstrated that berberine could ameliorate renal dysfunction in diabetic rats with nephropathy and inhibit fibronectin expression in mesangial cells cultured under high glucose. However, the molecular mechanisms have not been fully elucidated. The purpose of the present study was to investigate the effects of berberine on the nuclear factor-kappa B (NF-kappaB) activation, intercellular adhesion molecule-1, transforming growth factor-beta1 and fibronectin protein expression in renal tissue from alloxan-induced diabetic mice with renal damage. The distribution of NF-kappaB p65 in glomerulus and the degradation of I kappaB-alpha in renal cortex were examined by immunohistochemistry and Western blot, respectively. The protein expression of intercellular adhesion molecule-1, transforming growth factor-beta 1 and fibronectin in renal cortex were also detected by Western blot. Our results revealed that in alloxan-induced diabetic mice, the nuclear staining of NF-kappaB p65 was increased in glomerulus, whereas renal I kappaB-alpha protein was significantly reduced. The protein levels of intercellular adhesion molecule-1, transforming growth factor-beta 1 and fibronectin were upregulated in kidney from diabetic mice. After berberine treatment, the immunostaining of NF-kappaB was decreased, and the reduced degradation of I kappaB-alpha level was partially restored. The protein levels of intercellular adhesion molecule-1, transforming growth factor-beta 1 and fibronectin were all downregulated by berberine compared with diabetic model group. In conclusion, the ameliorative effects of berberine on extracellular matrix accumulation might associate with its inhibitory function on NF-kappaB signal pathway.
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ABSTRACT: Diabetes and diabetic nephropathy are complex diseases affected by genetic and environmental factors. Identification of the susceptibility genes and investigation of their roles may provide useful information for better understanding of the pathogenesis and for developing novel therapeutic approaches. Intercellular adhesion molecule 1 (ICAM1) is a cell surface glycoprotein expressed on endothelial cells and leukocytes in the immune system. The ICAM1 gene is located on chromosome 19p13 within the linkage region of diabetes. In the recent years, accumulating reports have implicated that genetic polymorphisms in the ICAM1 gene are associated with diabetes and diabetic nephropathy. Serum ICAM1 levels in diabetes patients and the icam1 gene expression in kidney tissues of diabetic animals are increased compared to the controls. Therefore, ICAM1 may play a role in the development of diabetes and diabetic nephropathy. In this review, we present genomic structure, variation, and regulation of the ICAM1 gene, summarized genetic and biological studies of this gene in diabetes and diabetic nephropathy and discussed about the potential application using ICAM1 as a biomarker and target for prediction and treatment of diabetes and diabetic nephropathy.Frontiers in Endocrinology 01/2012; 3:179.
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ABSTRACT: RhoA/Rho kinase (ROCK) signaling has been suggested to be involved in diabetic nephropathy (DN) pathogenesis. Altered expression of connexin43 (Cx43) has been found in kidneys of diabetic animals. Both of them have been found to regulate nuclear factor kappa-B (NF-κB) activation in high glucose-treated glomerular mesangial cells (GMCs). The aim of this study was to investigate the relationship between RhoA/ROCK signaling and Cx43 in the DN pathogenesis. We found that upregulation of Cx43 expression inhibited NF-κB p65 nuclear translocation induced by RhoA/ROCK signaling in GMCs. Inhibition of RhoA/ROCK signaling attenuated the high glucose-induced decrease in Cx43. F-actin accumulation and an enhanced interaction between zonula occludens-1 (ZO-1) and Cx43 were observed in high glucose-treated GMCs. ZO-1 depletion or disruption of F-actin formation also inhibited the reduction in Cx43 protein levels induced by high glucose. In conclusion, activated RhoA/ROCK signaling induces Cx43 degradation in GMCs cultured in high glucose, depending on F-actin regulation. Increased F-actin induced by RhoA/ROCK signaling promotes the association between ZO-1 and Cx43, which possibly triggered Cx43 endocytosis, a mechanism of NF-κB activation in high glucose-treated GMCs.Experimental cell research. 07/2014;
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ABSTRACT: BACKGROUND: Nuclear factor kappa-B (NF-kappaB) signalling plays an important role in diabetic nephropathy. Altered expression of connexin43 (Cx43) has been found in kidneys of diabetic animals. The aim of the current study was to investigate the role of Cx43 in the activation of NF-kappaB induced by high glucose in glomerular mesangial cells (GMCs) and to determine whether c-Src is involved in this process. RESULTS: We found that downregulation of Cx43 expression induced by high glucose activated NF-kappaB in GMCs. Orverexpression of Cx43 attenuated NF-kappaB p65 nuclear translocation induced by high glucose. High glucose inhibited the interaction between Cx43 and c-Src, and enhanced the interaction between c-Src and IkappaB-alpha. PP2, a c-Src inhibitor, also inhibited the tyrosine phosphorylation of IkappaB-alpha and NF-kappaB p65 nuclear translocation induced by high glucose. Furthermore, overexpression of Cx43 or inhibition of c-Src attenuated the upregulation of intercellular adhesion molecule-1 (ICAM-1), transforming growth factor-beta 1 (TGF-beta1) and fibronectin (FN) expression induced by high glucose. CONCLUSIONS: In conclusion, downregulation of Cx43 in GMCs induced by high glucose activates c-Src, which in turn promotes interaction between c-Src and IkappaB-alpha and contributes to NF-kappaB activation in GMCs, leading to renal inflammation.Cell Communication and Signaling 05/2013; 11(1):38. · 5.09 Impact Factor