Lipoxin A(4) inhibits transition of epithelial to mesenchymal cells in proximal tubules.
BACKGROUND
Previous studies showed that connective tissue growth factor (CTGF)-induced proliferation of lung fibroblasts and production of chemokines in mesangial cells could be inhibited by lipoxin A(4) (LXA(4)). It is speculated that LXA(4) could modulate the CTGF-induced epithelial to mesenchymal transition.


METHODS
The expressions of alpha-smooth muscle actin (alpha-SMA), E-cadherin, integrin-linked kinase (ILK), extracellular signal-regulated kinase 1/2 (ERK1/2), phosphatidylinositol 3-kinase (PI3-K), Akt and Smad signaling were assessed by Western blot and/or real-time RT-PCR, and activation of Ras or ILK by activity assay, expressions of alpha-SMA and zonula occludens-1 by immunofluorescence assay in proximal tubular epithelial cells (HK-2).


RESULTS
Pretreatment of HK-2 cells with LXA(4) inhibited the morphological fibroblast-like changes and alpha-SMA expression induced by CTGF but not by transforming growth factor-beta(1) (TGF-beta(1)). The expressions of E-cadherin and zonula occludens-1 reduced by CTGF but not by TGF-beta(1) were increased by LXA(4). LXA(4) inhibited the expression and activity of ILK and activation of Ras, ERK1/2, PI3-K and Akt in HK-2 cells stimulated by CTGF. LXA(4) did not affect TGF-beta(1)-induced expression of ILK, Smad-2/3 phosphorylation and Smad-2's binding to Smad-4 and subsequent nuclear translocation.


CONCLUSIONS
LXA(4) inhibits the tubular epithelial to mesenchymal transition, initiated by CTGF but not by TGF-beta(1), via downregulation of ILK, Ras/MEK/ERK1/2 and PI3-K/Akt-dependent signal pathway stimulated by CTGF.
Wu
Sheng-Hua
SH
Department of Pediatrics, The First Affiliated Hospital of Nanjing Medical University, China. kad-yc@163.com
Zhang
Yong-Mei
YM
Tao
Hui-Xian
HX
Dong
Ling
L
D002460:Cell Line; D055513:Connective Tissue Growth Factor / Q000378:metabolism; D015536:Down-Regulation; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D007687:Kidney Tubules, Proximal / Q000166:cytology*; D044045:Lipoxins / Q000378:metabolism* / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D044042:Receptors, Formyl Peptide / Q000235:genetics / Q000378:metabolism*; D044067:Receptors, Lipoxin / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D018631:ras Proteins / Q000097:blood / Q000378:metabolism
C105101:FPR2 protein, human; D044045:Lipoxins; D044042:Receptors, Formyl Peptide; D044067:Receptors, Lipoxin; D053773:Transforming Growth Factor beta1; C040527:lipoxin A4; D055513:Connective Tissue Growth Factor; D017346:Protein Serine-Threonine Kinases; D018631:ras Proteins