title: Curcumin inhibits transforming growth factor-β1-induced EMT via PPARγ pathway, not Smad pathway in renal tubular epithelial cells.
abstract: Tubulointerstitial fibrosis (TIF) is the final common pathway in the end-stage renal disease. Epithelial-to-mesenchymal transition (EMT) is considered a major contributor to the TIF by increasing the number of myofibroblasts. Curcumin, a polyphenolic compound derived from rhizomes of Curcuma, has been shown to possess potent anti-fibrotic properties but the mechanism remains elusive. We found that curcumin inhibited the EMT as assessed by reduced expression of α-SMA and PAI-1, and increased E-cadherin in TGF-β1 treated proximal tubular epithelial cell HK-2 cells. Both of the conventional TGF-β1/Smad pathway and non-Smad pathway were investigated. Curcumin reduced TGF-β receptor type I (TβR-I) and TGF-β receptor type II (TβR II), but had no effect on phosphorylation of Smad2 and Smad3. On the other hand, in non-Smad pathway curcumin reduced TGF-β1-induced ERK phosphorylation and PPARγ phosphorylation, and promoted nuclear translocation of PPARγ. Further, the effect of curcumin on α-SMA, PAI-1, E-cadherin, TβR I and TβR II were reversed by ERK inhibitor U0126 or PPARγ inhibitor BADGE, or PPARγ shRNA. Blocking PPARγ signaling pathway by inhibitor BADGE or shRNA had no effect on the phosphorylation of ERK whereas the suppression of ERK signaling pathway inhibited the phosphorylation of PPARγ. We conclude that curcumin counteracted TGF-β1-induced EMT in renal tubular epithelial cells via ERK-dependent and then PPARγ-dependent pathway.
authors.affiliation: Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Li
authors.forename: Yunman
authors.initials: Y
authors.lastname: Wang
authors.forename: Yujun
authors.initials: Y
authors.lastname: Liu
authors.forename: Qijing
authors.initials: Q
authors.lastname: Chen
authors.forename: Wencheng
authors.initials: W
authors.lastname: Fu
authors.forename: Hao
authors.initials: H
authors.lastname: Wang
authors.forename: Hui
authors.initials: H
authors.lastname: Cai
authors.forename: Wen
authors.initials: W
authors.lastname: Peng
authors.forename: Xuemei
authors.initials: X
authors.lastname: Zhang
mesh_terms: D000818:Animals; D002070:Butadienes / Q000494:pharmacology; D015820:Cadherins / Q000378:metabolism; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D003474:Curcumin / Q000494:pharmacology*; D004847:Epithelial Cells / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D007687:Kidney Tubules, Proximal / Q000166:cytology*; D009570:Nitriles / Q000494:pharmacology; D047495:PPAR gamma / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D051381:Rats; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051785:Smad Proteins / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology*
chemical_list: D002070:Butadienes; D015820:Cadherins; D009570:Nitriles; D047495:PPAR gamma; D017395:Plasminogen Activator Inhibitor 1; D047428:Protein Kinase Inhibitors; D018125:Receptors, Transforming Growth Factor beta; D051785:Smad Proteins; D053773:Transforming Growth Factor beta1; C113580:U 0126; D017346:Protein Serine-Threonine Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II; C000625843:Tgfbr1 protein, rat; D003474:Curcumin
references.citation: Nature. 2003 Oct 9;425(6958):577-84
references.pmid: 14534577
references.citation: Am J Physiol Renal Physiol. 2009 May;296(5):F1146-57
references.pmid: 19225048
references.citation: J Mol Med (Berl). 2004 Mar;82(3):175-81
references.pmid: 14752606
references.citation: Mol Cell Biol. 2002 Apr;22(8):2607-19
references.pmid: 11909955
references.citation: J Cell Sci. 2005 Aug 15;118(Pt 16):3573-84
references.pmid: 16105881
references.citation: Kidney Int. 2004 Jul;66(1):112-20
references.pmid: 15200418
references.citation: Am J Physiol Renal Physiol. 2005 Nov;289(5):F1153-8
references.pmid: 15886275
references.citation: Am J Physiol Gastrointest Liver Physiol. 2005 Mar;288(3):G447-56
references.pmid: 15486348
references.citation: J Cell Physiol. 2012 Feb;227(2):493-507
references.pmid: 21465481
references.citation: Lab Invest. 2009 Jan;89(1):47-58
references.pmid: 19002105
references.citation: Neoplasia. 2004 Sep-Oct;6(5):603-10
references.pmid: 15548370
references.citation: Clin Sci (Lond). 2009 Jan;116(1):17-26
references.pmid: 19037881
references.citation: Breast Cancer Res. 2003;5(6):R187-98
references.pmid: 14580254
references.citation: Biochim Biophys Acta. 2009 Jul;1793(7):1165-73
references.pmid: 19339207
references.citation: Reprod Toxicol. 2009 Jun;27(3-4):246-257
references.pmid: 18996469
references.citation: Acta Biochim Biophys Sin (Shanghai). 2009 Apr;41(4):263-72
references.pmid: 19352540
references.citation: Zhongguo Zhong Xi Yi Jie He Za Zhi. 2011 Sep;31(9):1224-8
references.pmid: 22013801
references.citation: BMC Complement Altern Med. 2012 Sep 16;12:156
references.pmid: 22978413
references.citation: Life Sci. 2006 Mar 27;78(18):2081-7
references.pmid: 16413584
references.citation: Urology. 2006 Feb;67(2):440-6
references.pmid: 16461119
references.citation: Adv Immunol. 2000;75:115-57
references.pmid: 10879283
references.citation: Am J Physiol Lung Cell Mol Physiol. 2007 Sep;293(3):L525-34
references.pmid: 17631612
references.citation: Gene Ther Mol Biol. 2009 Apr 1;13(1):20-25
references.pmid: 19644570
references.citation: Am J Pathol. 2001 Oct;159(4):1465-75
references.pmid: 11583974
references.citation: Nephrology (Carlton). 2005 Oct;10 Suppl:S40-3
references.pmid: 16174287
references.citation: Am J Nephrol. 2010;31(4):332-41
references.pmid: 20160437
references.citation: J Pharmacol Exp Ther. 2006 May;317(2):500-5
references.pmid: 16424149
references.citation: Biochimie. 2005 Jan;87(1):33-8
references.pmid: 15733734
references.citation: Nephrology (Carlton). 2005 Feb;10(1):48-56
references.pmid: 15705182
references.citation: Annu Rev Med. 2002;53:409-35
references.pmid: 11818483
references.citation: Kidney Int. 2001 May;59(5):1899-910
references.pmid: 11318962
references.citation: Dev Cell. 2009 Mar;16(3):329-43
references.pmid: 19289080
references.citation: J Clin Invest. 2003 Dec;112(12):1776-84
references.pmid: 14679171
references.citation: Eur J Pharmacol. 2011 Mar 1;654(1):92-9
references.pmid: 21187084
references.citation: Br J Pharmacol. 2008 Feb;153(3):557-67
references.pmid: 17965732
references.citation: Cell Signal. 2003 Apr;15(4):355-66
references.pmid: 12618210
references.citation: PPAR Res. 2008;2008:183108
references.pmid: 19283081
references.citation: J Korean Med Sci. 2010 Jan;25(1):35-41
references.pmid: 20052345
references.citation: PPAR Res. 2008;2008:309469
references.pmid: 18596912
references.citation: Oncogene. 2005 Aug 29;24(37):5764-74
references.pmid: 16123809
references.citation: Nephrol Dial Transplant. 2008 Sep;23(9):2750-60
references.pmid: 18388116
references.citation: Br J Pharmacol. 2000 Sep;131(2):169-72
references.pmid: 10991907