Zinc Attenuates Tubulointerstitial Fibrosis in Diabetic Nephropathy Via Inhibition of HIF Through PI-3K Signaling

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• 作者：Xiuli Zhang ; Dan Liang ; Jingyue Fan ; Xu Lian ; Yue Zhao…
• 关键词：Zinc ; Epithelial ; to ; mesenchymal transition ; Diabetic nephropathy ; Tubulointerstitial fibrosis ; HIF ; 1α ; PI3K/Akt/GSK ; 3β signaling pathway
• 刊名：Biological Trace Element Research
• 出版年：2016
• 出版时间：October 2016
• 年：2016
• 卷：173
• 期：2
• 页码：372-383
• 全文大小：3,222 KB
• 刊物主题：Biochemistry, general; Biotechnology; Nutrition; Oncology;
• 出版者：Springer US
• ISSN：1559-0720
• 卷排序：173

文摘

Evidence has demonstrated that hypoxia may have a central pathogenic mechanism in the development of diabetic nephropathy (DN). Epithelial-to-mesenchymal transition (EMT) of mature tubular epithelial cells in kidney is a contributor to the renal accumulation of matrix protein in DN and is highly associated with the progression of tubulointerstitial fibrosis. Zinc (Zn) has anti-fibrosis effects in liver and lungs. In the present study, we aimed to investigate the effect of Zn on renal tubulointerstitial fibrosis especially under hypoxic conditions and its association with DN. We found that Zn treatment blockaded tubular EMT and attenuated renal tubulointerstitial fibrosis by downregulation of hypoxia-inducible factor alpha (HIF-1α) in the kidneys of diabetic streptozotocin-treated mice. High glucose (HG)/hypoxic conditions stimulated EMT in renal tubular cells as indicated by the significant decrease in epithelial marker E-cadherin and ZO-1 while the increase in mesenchymal markers α-smooth muscle actin (α-SMA). Zn supplement mainly prevented HG/hypoxic-induced HIF-1α accumulation and EMT marker changes. In co-treatment Zn with PI3K/Akt/GSK-3β signaling pathway, inhibitor LY294002 prevented HG/hypoxic-induced HIF-1α increase and EMT changes, suggesting that Zn may mediate HG/hypoxic-induced EMT through PI3K/Akt/GSK-3β pathway. Therefore, we concluded that Zn had an important anti-fibrosis role under HG/hypoxic conditions, and a novel mechanism contributing to Zn protection on renal tubular epithelial cells from HG/hypoxia-induced EMT through activation of PI3K/Akt/GSK-3β signaling pathway, which subsequently leads to the downregulation of the expression of HIF-1α.