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Role of ERK1/2 and p38 Mitogen-Activated Protein Kinases in the Regulation of Thrombospondin-1 by TGF-1 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^* and Yuri Y. Sautin^*

^* Division of Nephrology, Hypertension and Transplantation, University of Florida, Gainesville, Florida; Division of Nephrology-Medicine, Baylor College of Medicine, Houston, Texas; Ludwig Institute for Cancer Research, Royal Melbourne Hospital, Victoria, Australia; Division of Nephrology, Ewha Women’s University Hospital, Seoul, Korea; ^|| Scios Inc., Sunnyvale, California; and, ^¶ Division of Nephrology, Department of Medicine, Albert Einstein College of Medicine, Bronx, New York

Address correspondence to: Dr. Takahiko Nakagawa, Division of Nephrology, Hypertension and Transplantation, University of Florida, P.O. Box 100224, Gainesville, FL 32610-0224. Phone: 352-392-4008; Fax: 352-392-3581; E-mail:nakagt{at}medicine.ufl.edu

Received for publication August 19, 2004. Accepted for publication January 5, 2005.

Thrombospondin-1 (TSP-1) inhibits angiogenesis and activates latent TGF-1, 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-1 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-1 activated both ERK1/2 and p38 in the rat proximal tubular cell line NRK52E. Blocking ERK1/2 and p38 inhibited TGF-1–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-1–induced Smad2 activation, inhibition of Smad2 by Smad7 overexpression inhibited the phosphorylation of ERK1/2 but not p38 in response to TGF-1. Similar results were observed using mouse fibroblasts from Smad2 knockout embryos, in that TGF-1 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-1. 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-1, this provides an important insight to the mechanism by which TGF-1 may mediate interstitial fibrosis and progressive renal disease.

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