TY - JOUR
T1 - Role of ERK1/2 and p38 mitogen-activated protein kinases in the regulation of thrombospondin-1 by TGF-β1 in rat proximal tubular cells and mouse fibroblasts
AU - Nakagawa, Takahiko
AU - Lan, Hui Y.
AU - Glushakova, Olena
AU - Zhu, Hong J.
AU - Kang, Duk Hee
AU - Schreiner, George F.
AU - Böttinger, Erwin P.
AU - Johnson, Richard J.
AU - Sautin, Yuri Y.
PY - 2005
Y1 - 2005
N2 - Thrombospondin-1 (TSP-1) inhibits angiogenesis and activates latent TGF-β1, both of which are strongly associated with progression of renal disease. Recently, it was reported that Smad2 but not Smad3 regulates TSP-1 expression in response to TGF-β1 in rat tubular epithelial cells as well as in mouse fibroblasts. This study investigated the role of ERK1/2 and p38 mitogen-activated protein kinases (MAPK). TGF-β1 activated both ERK1/2 and p38 in the rat proximal tubular cell line NRK52E. Blocking ERK1/2 and p38 inhibited TGF-β1-induced TSP-1 mRNA and protein expression. Next, the cross-talk between Smad2 and ERK1/2 or p38 was examined. Whereas blocking of ERK1/2 or p38 failed to inhibit TGF-β1-induced Smad2 activation, inhibition of Smad2 by Smad7 overexpression inhibited the phosphorylation of ERK1/2 but not p38 in response to TGF-β1. Similar results were observed using mouse fibroblasts from Smad2 knockout embryos, in that TGF-β1 was able to activate p38 but not ERK1/2 in this cell line. In conclusion, TSP-1 expression is regulated by both ERK1/2 and p38 MAPK in rat proximal tubular cells and mouse fibroblasts in response to TGF-β1. The ERK1/2 activation is dependent on Smad2 activation, whereas the p38 activation occurs independent of Smad2. Because TSP-1 is a major antiangiogenic molecule and an activator of TGF-β1, this provides an important insight to the mechanism by which TGF-β1 may mediate interstitial fibrosis and progressive renal disease.
AB - Thrombospondin-1 (TSP-1) inhibits angiogenesis and activates latent TGF-β1, both of which are strongly associated with progression of renal disease. Recently, it was reported that Smad2 but not Smad3 regulates TSP-1 expression in response to TGF-β1 in rat tubular epithelial cells as well as in mouse fibroblasts. This study investigated the role of ERK1/2 and p38 mitogen-activated protein kinases (MAPK). TGF-β1 activated both ERK1/2 and p38 in the rat proximal tubular cell line NRK52E. Blocking ERK1/2 and p38 inhibited TGF-β1-induced TSP-1 mRNA and protein expression. Next, the cross-talk between Smad2 and ERK1/2 or p38 was examined. Whereas blocking of ERK1/2 or p38 failed to inhibit TGF-β1-induced Smad2 activation, inhibition of Smad2 by Smad7 overexpression inhibited the phosphorylation of ERK1/2 but not p38 in response to TGF-β1. Similar results were observed using mouse fibroblasts from Smad2 knockout embryos, in that TGF-β1 was able to activate p38 but not ERK1/2 in this cell line. In conclusion, TSP-1 expression is regulated by both ERK1/2 and p38 MAPK in rat proximal tubular cells and mouse fibroblasts in response to TGF-β1. The ERK1/2 activation is dependent on Smad2 activation, whereas the p38 activation occurs independent of Smad2. Because TSP-1 is a major antiangiogenic molecule and an activator of TGF-β1, this provides an important insight to the mechanism by which TGF-β1 may mediate interstitial fibrosis and progressive renal disease.
UR - http://www.scopus.com/inward/record.url?scp=24344491188&partnerID=8YFLogxK
U2 - 10.1681/ASN.2004080689
DO - 10.1681/ASN.2004080689
M3 - Article
C2 - 15716330
AN - SCOPUS:24344491188
SN - 1046-6673
VL - 16
SP - 899
EP - 904
JO - Journal of the American Society of Nephrology
JF - Journal of the American Society of Nephrology
IS - 4
ER -