title: Urotensin II Induces ER Stress and EMT and Increase Extracellular Matrix Production in Renal Tubular Epithelial Cell in Early Diabetic Mice.
abstract: OBJECTIVE
  Urotensin II (UII) and its receptor are highly expressed in the kidney tissue of patients with diabetic nephropathy (DN). The aim of this study is to examine the roles of UII in the induction of endoplasmic reticulum stress (ER stress) and Epithelial-mesenchymal transition (EMT) in DN in vivo and in vitro.
  
  
  METHODS
  Kidney tissues were collected from patients with DN. C57BL/6 mice and mice with UII receptor knock out were injected with two consecutive doses of streptozotocin to induce diabetes and were sacrificed at 3th week for in vivo study. HK-2 cells in vitro were cultured and treated with UII. Markers of ER stress and EMT, fibronectin and type IV collagen were detected by immunohistochemistry, real time PCR and western blot.
  
  
  RESULTS
  We found that the expressions of protein of UII, GRP78, CHOP, ALPHA-SMA, fibronectin and type IV collagen were upregulated while E-cadherin protein was downregulated as shown by immunohistochemistry or western blot analysis in kidney of diabetic mice in comparison to normal control; moreover expressions of GRP78, CHOP, ALPHA-SMA, fibronectin and type IV collagen were inhibited while E-caherin expression was enhanced in kidney in diabetic mice with UII receptor knock out in comparison to C57BL/6 diabetic mice. In HK-2 cells, UII induced upregulation of GRP78, CHOP, ALPHA-SMA, fibroblast-specifc protein 1(FSP-1), fibronectin and type collagen and downregulation of E-cadherin. UII receptor antagonist can block UII-induced ER stress and EMT; moreover, 4-PBA can inhibit the mRNA expression of ALPHA-SMA and FSP1 induced by UII in HK-2 cells.
  
  
  CONCLUSIONS
  We are the first to verify UII induces ER stress and EMT and increase extracellular matrix production in renal tubular epithelial cell in early diabetic mice. Moreover, UII may induce renal tubular epithelial EMT via triggering ER stress pathway in vitro, which might be the new pathogenic pathway for the development of renal fibrosis in DN.
authors.affiliation: Department of Nephrology, Peking University Third Hospital, Peking University Health Science Center, Beijing, China.
authors.forename: Xin-Xin
authors.initials: XX
authors.lastname: Pang
authors.forename: Qiong
authors.initials: Q
authors.lastname: Bai
authors.forename: Fei
authors.initials: F
authors.lastname: Wu
authors.forename: Guan-Jong
authors.initials: GJ
authors.lastname: Chen
authors.forename: Ai-Hua
authors.initials: AH
authors.lastname: Zhang
authors.forename: Chao-Shu
authors.initials: CS
authors.lastname: Tang
mesh_terms: D000818:Animals; D002460:Cell Line; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000473:pathology; D003928:Diabetic Nephropathies / Q000378:metabolism / Q000473:pathology*; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D005109:Extracellular Matrix / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007684:Kidney Tubules / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D014579:Urotensins / Q000494:pharmacology*
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; C000717248:Hspa5 protein, mouse; D014579:Urotensins; C029677:urotensin II