Angiotensin II induces thrombospondin-1 production in human mesangial cells via p38 MAPK and JNK: a mechanism for activation of latent TGF-beta1.
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-beta1 complex. Therefore, we examined whether the ANG II-induced activation of latent TGF-beta1 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-beta1 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-beta1 in HMC operates via TSP-1. Furthermore, ANG II-induced TSP-1 production is dependent on p38 MAPK and JNK signaling.
Department of Molecular and Internal Medicine, Graduate School of Biomedical Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima City 734-8551, Japan.
Takayuki
T
Naito
Takao
T
Masaki
David J
DJ
Nikolic-Paterson
Chie
C
Tanji
Noriaki
N
Yorioka
Nobuoki
N
Kohno
D000804:Angiotensin II / Q000494:pharmacology*; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology; D015870:Gene Expression / Q000187:drug effects / Q000502:physiology; D005920:Glomerular Mesangium / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D020935:MAP Kinase Signaling System / Q000502:physiology; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics; D044139:Receptor, Angiotensin, Type 2 / Q000235:genetics; D019700:Thrombospondin 1 / Q000235:genetics*; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D053773:Transforming Growth Factor beta1; D014471:Umbilical Veins / Q000166:cytology; D014662:Vasoconstrictor Agents / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases
D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; C508960:TGFB1 protein, human; D019700:Thrombospondin 1; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D048031:JNK Mitogen-Activated Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases