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Am J Physiol Renal Physiol 286: F278-F287, 2004. First published October 28, 2003; doi:10.1152/ajprenal.00139.2003
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Angiotensin II induces thrombospondin-1 production in human mesangial cells via p38 MAPK and JNK: a mechanism for activation of latent TGF-{beta}1

Takayuki Naito,1 Takao Masaki,1 David J. Nikolic-Paterson,2 Chie Tanji,1 Noriaki Yorioka,1 and Nobuoki Kohno1

1Department of Molecular and Internal Medicine, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima 734-8551, Japan; and 2Department of Nephrology and Monash University Department of Medicine, Monash Medical Centre, Clayton, Victoria 3168, Australia

Submitted 14 April 2003 ; accepted in final form 19 October 2003

ANG II induces secretion and activation of transforming growth factor-{beta} (TGF-{beta}) by glomerular mesangial cells. However, the mechanisms that operate this are unclear. Thrombospondin-1 (TSP-1), which is produced by mesangial cells in damaged glomeruli, is one of several molecules known to activate the latent TGF-{beta}1 complex. Therefore, we examined whether the ANG II-induced activation of latent TGF-{beta}1 in human mesangial cells (HMC) operates via TSP-1. The addition of ANG II (1-100 nM) to HMC significantly increased TSP-1 mRNA within 6 h, followed by an increase in TSP-1 protein production as shown by Western blot analysis of cells and immunoassay of the culture supernatant. Production of ANG II-induced TSP-1 mRNA and protein was completely inhibited by an ANG II type 1 (AT1)-receptor antagonist but was unaffected by an AT2-receptor antagonist. Use of a TSP-1-specific blocking peptide demonstrated that the ANG II-induced activation of latent TGF-{beta}1 operates via TSP-1. Next, we investigated the role of ERK1/2, p38 MAPK, and JNK in ANG II-induced TSP-1 production in HMC. The addition of the upstream ERK1/2 inhibitor PD-98059 did not affect ANG II-induced TSP-1 production, whereas addition of either the p38 MAPK inhibitor SB-203580 or the JNK inhibitor SP-600125 significantly reduced TSP-1 production. In conclusion, this study has demonstrated that ANG II-induced activation of latent TGF-{beta}1 in HMC operates via TSP-1. Furthermore, ANG II-induced TSP-1 production is dependent on p38 MAPK and JNK signaling.

angiotensin II type 1 and type 2 receptor; extracellular signal-regulated kinase 1/2; thrombospondin-1 blocking peptide


Address for reprint requests and other correspondence: T. Masaki, Dept. of Molecular and Internal Medicine, Graduate School of Biomedical Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima City 734-8551, Japan (E-mail: masaki{at}hiroshima-u.ac.jp).




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