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Activation of Src Mediates PDGF-Induced Smad1 Phosphorylation and Contributes to the Progression of Glomerulosclerosis in Glomerulonephritis

Platelet-derived growth factor (PDGF) plays critical roles in mesangial cell (MC) proliferation in mesangial proliferative glomerulonephritis. We showed previously that Smad1 contributes to PDGF-dependent proliferation of MCs, but the mechanism by which Smad1 is activated by PDGF is not precisely kn...

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Autores principales: Mima, Akira, Abe, Hideharu, Nagai, Kojiro, Arai, Hidenori, Matsubara, Takeshi, Araki, Makoto, Torikoshi, Kazuo, Tominaga, Tatsuya, Iehara, Noriyuki, Fukatsu, Atsushi, Kita, Toru, Doi, Toshio
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3062564/
https://www.ncbi.nlm.nih.gov/pubmed/21445358
http://dx.doi.org/10.1371/journal.pone.0017929
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author Mima, Akira
Abe, Hideharu
Nagai, Kojiro
Arai, Hidenori
Matsubara, Takeshi
Araki, Makoto
Torikoshi, Kazuo
Tominaga, Tatsuya
Iehara, Noriyuki
Fukatsu, Atsushi
Kita, Toru
Doi, Toshio
author_facet Mima, Akira
Abe, Hideharu
Nagai, Kojiro
Arai, Hidenori
Matsubara, Takeshi
Araki, Makoto
Torikoshi, Kazuo
Tominaga, Tatsuya
Iehara, Noriyuki
Fukatsu, Atsushi
Kita, Toru
Doi, Toshio
author_sort Mima, Akira
collection PubMed
description Platelet-derived growth factor (PDGF) plays critical roles in mesangial cell (MC) proliferation in mesangial proliferative glomerulonephritis. We showed previously that Smad1 contributes to PDGF-dependent proliferation of MCs, but the mechanism by which Smad1 is activated by PDGF is not precisely known. Here we examined the role of c-Src tyrosine kinase in the proliferative change of MCs. Experimental mesangial proliferative glomerulonephritis (Thy1 GN) was induced by a single intravenous injection of anti-rat Thy-1.1 monoclonal antibody. In Thy1 GN, MC proliferation and type IV collagen (Col4) expression peaked on day 6. Immunohistochemical staining for the expression of phospho-Src (pSrc), phospho-Smad1 (pSmad1), Col4, and smooth muscle α-actin (SMA) revealed that the activation of c-Src and Smad1 signals in glomeruli peaked on day 6, consistent with the peak of mesangial proliferation. When treated with PP2, a Src inhibitor, both mesangial proliferation and sclerosis were significantly reduced. PP2 administration also significantly reduced pSmad1, Col4, and SMA expression. PDGF induced Col4 synthesis in association with increased expression of pSrc and pSmad1 in cultured MCs. In addition, PP2 reduced Col4 synthesis along with decreased pSrc and pSmad1 protein expression in vitro. Moreover, the addition of siRNA against c-Src significantly reduced the phosphorylation of Smad1 and the overproduction of Col4. These results provide new evidence that the activation of Src/Smad1 signaling pathway plays a key role in the development of glomerulosclerosis in experimental glomerulonephritis.
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spelling pubmed-30625642011-03-28 Activation of Src Mediates PDGF-Induced Smad1 Phosphorylation and Contributes to the Progression of Glomerulosclerosis in Glomerulonephritis Mima, Akira Abe, Hideharu Nagai, Kojiro Arai, Hidenori Matsubara, Takeshi Araki, Makoto Torikoshi, Kazuo Tominaga, Tatsuya Iehara, Noriyuki Fukatsu, Atsushi Kita, Toru Doi, Toshio PLoS One Research Article Platelet-derived growth factor (PDGF) plays critical roles in mesangial cell (MC) proliferation in mesangial proliferative glomerulonephritis. We showed previously that Smad1 contributes to PDGF-dependent proliferation of MCs, but the mechanism by which Smad1 is activated by PDGF is not precisely known. Here we examined the role of c-Src tyrosine kinase in the proliferative change of MCs. Experimental mesangial proliferative glomerulonephritis (Thy1 GN) was induced by a single intravenous injection of anti-rat Thy-1.1 monoclonal antibody. In Thy1 GN, MC proliferation and type IV collagen (Col4) expression peaked on day 6. Immunohistochemical staining for the expression of phospho-Src (pSrc), phospho-Smad1 (pSmad1), Col4, and smooth muscle α-actin (SMA) revealed that the activation of c-Src and Smad1 signals in glomeruli peaked on day 6, consistent with the peak of mesangial proliferation. When treated with PP2, a Src inhibitor, both mesangial proliferation and sclerosis were significantly reduced. PP2 administration also significantly reduced pSmad1, Col4, and SMA expression. PDGF induced Col4 synthesis in association with increased expression of pSrc and pSmad1 in cultured MCs. In addition, PP2 reduced Col4 synthesis along with decreased pSrc and pSmad1 protein expression in vitro. Moreover, the addition of siRNA against c-Src significantly reduced the phosphorylation of Smad1 and the overproduction of Col4. These results provide new evidence that the activation of Src/Smad1 signaling pathway plays a key role in the development of glomerulosclerosis in experimental glomerulonephritis. Public Library of Science 2011-03-22 /pmc/articles/PMC3062564/ /pubmed/21445358 http://dx.doi.org/10.1371/journal.pone.0017929 Text en Mima et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Mima, Akira
Abe, Hideharu
Nagai, Kojiro
Arai, Hidenori
Matsubara, Takeshi
Araki, Makoto
Torikoshi, Kazuo
Tominaga, Tatsuya
Iehara, Noriyuki
Fukatsu, Atsushi
Kita, Toru
Doi, Toshio
Activation of Src Mediates PDGF-Induced Smad1 Phosphorylation and Contributes to the Progression of Glomerulosclerosis in Glomerulonephritis
title Activation of Src Mediates PDGF-Induced Smad1 Phosphorylation and Contributes to the Progression of Glomerulosclerosis in Glomerulonephritis
title_full Activation of Src Mediates PDGF-Induced Smad1 Phosphorylation and Contributes to the Progression of Glomerulosclerosis in Glomerulonephritis
title_fullStr Activation of Src Mediates PDGF-Induced Smad1 Phosphorylation and Contributes to the Progression of Glomerulosclerosis in Glomerulonephritis
title_full_unstemmed Activation of Src Mediates PDGF-Induced Smad1 Phosphorylation and Contributes to the Progression of Glomerulosclerosis in Glomerulonephritis
title_short Activation of Src Mediates PDGF-Induced Smad1 Phosphorylation and Contributes to the Progression of Glomerulosclerosis in Glomerulonephritis
title_sort activation of src mediates pdgf-induced smad1 phosphorylation and contributes to the progression of glomerulosclerosis in glomerulonephritis
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3062564/
https://www.ncbi.nlm.nih.gov/pubmed/21445358
http://dx.doi.org/10.1371/journal.pone.0017929
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