title: Zinc Attenuates Tubulointerstitial Fibrosis in Diabetic Nephropathy Via Inhibition of HIF Through PI-3K Signaling.
abstract: 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.
authors.affiliation: Key Laboratory of Medical Cell Biology, Ministry of Education, Shenyang, Liaoning, 110001, People's Republic of China.|Department of Nephrology, Benxi Center Hospital, Benxi, Liaoning, 117000, People's Republic of China.
authors.forename: Xiuli
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Troops of 95935 Unit, Harbin, Heilongjiang, 158000, People's Republic of China.
authors.forename: Dan
authors.initials: D
authors.lastname: Liang
authors.affiliation: Department of Cardiology, Shuangcheng District People's Hospital, Harbin, 150100, People's Republic of China.
authors.forename: Jingyue
authors.initials: J
authors.lastname: Fan
authors.affiliation: Department of Endocrinology, The Affiliated Hospital of Mudanjiang Medical University, Mudanjiang, Heilongjiang, 157000, People's Republic of China.
authors.forename: Xu
authors.initials: X
authors.lastname: Lian
authors.affiliation: Key Laboratory of Medical Cell Biology, Ministry of Education, Shenyang, Liaoning, 110001, People's Republic of China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Key Laboratory of Medical Cell Biology, Ministry of Education, Shenyang, Liaoning, 110001, People's Republic of China.
authors.forename: Xuemei
authors.initials: X
authors.lastname: Wang
authors.affiliation: Key Laboratory of Medical Cell Biology, Ministry of Education, Shenyang, Liaoning, 110001, People's Republic of China. chizhihong2015@126.com.|Department of Histology and Embryology, Liaoning Medical University, Jinzhou, 121001, People's Republic of China. chizhihong2015@126.com.
authors.forename: Zhi-Hong
authors.initials: ZH
authors.lastname: Chi
authors.affiliation: Department of Pathophysiology, China Medical University, No. 77, Puhe Road, Shenbei New Area, Shenyang, Liaoning, 110001, People's Republic of China.
authors.forename: Ping
authors.initials: P
authors.lastname: Zhang
mesh_terms: D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D003928:Diabetic Nephropathies / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D005355:Fibrosis; D000071679:Glycogen Synthase Kinase 3 beta / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007684:Kidney Tubules / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D015032:Zinc / Q000494:pharmacology*
chemical_list: C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D019869:Phosphatidylinositol 3-Kinases; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D015032:Zinc
keywords: Diabetic nephropathy; Epithelial-to-mesenchymal transition; HIF-1α; PI3K/Akt/GSK-3β signaling pathway; Tubulointerstitial fibrosis; Zinc