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Am J Physiol Renal Physiol (October 28, 2003). doi:10.1152/ajprenal.00139.2003
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Submitted on April 4, 2003
Accepted on October 19, 2003

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 Naito1, Takao Masaki1*, David J. Nikolic-Paterson2, Chie Tanji1, Noriaki Yorioka1, and Nobuoki Kohno1

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

* To whom correspondence should be addressed. E-mail: masaki{at}hiroshima-u.ac.jp.

Angiotensin II (Ang II) induces secretion and activation of transforming growth factor-{beta} (TGF-{beta}) by glomerular mesangial cells. However, the mechanisms by which operates 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 to 100 nM) to HMC significantly increased TSP-1 mRNA within 6 hours followed by an increase in TSP-1 protein production as shown by western blot of cells and immunoassay of culture supernatant. Ang II-induced TSP-1 mRNA and protein production 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 extracellular signal-regulated kinase (ERK) 1/2, p38 mitogen-activated protein kinase (p38 MAPK) and c-Jun N-terminal kinase (JNK) in the Ang II-induced TSP-1 production in HMC. Addition of the upstream ERK1/2 inhibitor PD98059 did not affect Ang II induced TSP-1 production, whereas addition of either the p38 MAPK inhibitor 203580 or the JNK inhibitor SP600125 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 upon p38 MAPK and JNK signaling.




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