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

Takahiko Nakagawa, Hui Y. Lan, Olena Glushakova, Hong J. Zhu, Duk Hee Kang, George F. Schreiner, Erwin P. Böttinger, Richard J. Johnson, Yuri Y. Sautin

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48 Scopus citations

Abstract

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.

Original languageEnglish
Pages (from-to)899-904
Number of pages6
JournalJournal of the American Society of Nephrology
Volume16
Issue number4
DOIs
StatePublished - 2005

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