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Am J Physiol Renal Physiol 280: F495-F504, 2001;
0363-6127/01 $5.00
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Vol. 280, Issue 3, F495-F504, March 2001

Stimulation of pro-alpha 1(I) collagen by TGF-beta 1 in mesangial cells: role of the p38 MAPK pathway

Beek Yoke Chin1, Amir Mohsenin2, Su Xia Li3, Augustine M. K. Choi4, and Mary E. Choi2

1 Toxicological Sciences, Environmental Health Sciences, and 3 Department of Medicine, The Johns Hopkins Medical Institutions, Baltimore, Maryland 21205; and Sections of 4 Pulmonary and Critical Care Medicine and 2 Nephrology, Department of Internal Medicine, Yale University School of Medicine and the Veterans Affairs Connecticut Healthcare Systems, New Haven, Connecticut 06520

Transforming growth factor-beta 1 (TGF-beta 1) is a potent inducer of extracellular matrix protein synthesis and a key mediator of renal fibrosis. However, the intracellular signaling mechanisms by which TGF-beta 1 stimulates this process remain incompletely understood. In this report, we examined the role of a major stress-activated intracellular signaling cascade, belonging to the mitogen-activated protein kinase (MAPK) superfamily, in mediating TGF-beta 1 responses in rat glomerular mesangial cells, using dominant-negative inhibition of TGF-beta 1 signaling receptors. We first stably transfected rat glomerular mesangial cells with a kinase-deleted mutant TGF-beta type II receptor (Tbeta R-IIM) designed to inhibit TGF-beta 1 signaling in a dominant-negative fashion. Next, expression of Tbeta R-IIM mRNA was confirmed by Northern analysis. Cell surface expression and ligand binding of Tbeta R-IIM protein were demonstrated by affinity cross-linking with 125I-labeled-TGF-beta 1. TGF-beta 1 rapidly induced p38 MAPK phosphorylation in wild-type and empty vector (pcDNA3)-transfected control mesangial cells. Interestingly, transfection with dominant-negative Tbeta R-IIM failed to block TGF-beta 1-induced p38 MAPK phosphorylation. Moreover, dominant-negative Tbeta R-IIM failed to block TGF-beta 1-stimulated pro-alpha 1(I) collagen mRNA expression and cellular protein synthesis, whereas TGF-beta 1-induced extracellular signal-regulated kinase (ERK) 1/ERK2 activation and antiproliferative responses were blocked by Tbeta R-IIM. In the presence of a specific inhibitor of p38 MAPK, SB-203580, TGF-beta 1 was unable to stimulate pro-alpha 1(I) collagen mRNA expression in the control and Tbeta R-IIM-transfected mesangial cells. Finally, we confirmed that both p38 MAPK activation and pro-alpha 1(I) collagen stimulation were TGF-beta 1 effects that were abrogated by dominant-negative inhibition of TGF-beta type I receptor. Thus we show first demonstration of p38 MAPK activation by TGF-beta 1 in mesangial cells, and, given the rapid kinetics, this TGF-beta 1 effect is likely a direct one. Furthermore, our findings suggest that the p38 MAPK pathway functions as a component in the signaling of pro-alpha 1(I) collagen induction by TGF-beta 1 in mesangial cells.

transforming growth factor-beta receptor; signal transduction; mitogen-activated protein kinase; matrix


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