title: Hepatocyte growth factor attenuates transforming growth factor-β-angiotensin II crosstalk through inhibition of the PTEN/Akt pathway.
abstract: Both angiotensin II (Ang II) and transforming growth factor (TGF)-β1 are thought to be involved in the progression of chronic kidney disease. In contrast, hepatocyte growth factor (HGF) counteracts the actions of Ang II and TGF-β1. Therefore, in this study, we investigated the molecular mechanisms of how HGF antagonizes the Ang II-TGF-β axis in renal cells. In cultured human mesangial cells, TGF-β1 increased angiotensin type 1 receptor (AT(1)R) mRNA, mainly dependent on the Akt/phosphatidylinositol 3-kinase signaling pathway. Furthermore, TGF-β1 decreased the expression and phosphatase activity of phosphatase and tensin homolog, deleted on chromosome 10 (PTEN), a negative regulator of the phosphatidylinositol 3-kinase/Akt pathway. These data revealed positive feedback of the Ang II-TGF-β pathway, because Ang II increased TGF-β expression. In contrast, HGF significantly attenuated the increase in AT(1)R gene expression, and inhibited the decrease in PTEN induced by TGF-β1. Of importance, a PTEN-specific inhibitor significantly attenuated the reduction in TGF-β1-induced AT(1)R expression by HGF. These data suggest that HGF attenuated TGF-β1-induced AT(1)R expression through the PTEN/Akt pathway. To investigate this hypothesis, we performed in vivo experiments in mice with increased circulating levels of HGF produced by transgenically expressing HGF under control of a cardiac-specific transgene (HGF-Tg). In HGF-Tg mice, renal injury and fibrosis were significantly decreased, associated with reduction in AT(1)R expression and increase in PTEN after Ang II infusion, as compared with control mice. Moreover, these renal protective effects were abrogated by a neutralizing antibody against HGF. Thus, the present study demonstrated that HGF counteracts the vicious cycle of Ang II-TGF-β1-AT(1)R, mediating the inhibition of PTEN.
authors.affiliation: Department of Clinical Gene Therapy, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita 565-0871, Japan.
authors.forename: Kazuma
authors.initials: K
authors.lastname: Iekushi
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Taniyama
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kusunoki
authors.forename: Junya
authors.initials: J
authors.lastname: Azuma
authors.forename: Fumihiro
authors.initials: F
authors.lastname: Sanada
authors.forename: Keita
authors.initials: K
authors.lastname: Okayama
authors.forename: Nobutaka
authors.initials: N
authors.lastname: Koibuchi
authors.forename: Masaaki
authors.initials: M
authors.lastname: Iwabayashi
authors.forename: Hiromi
authors.initials: H
authors.lastname: Rakugi
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Morishita
mesh_terms: D000804:Angiotensin II / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D017228:Hepatocyte Growth Factor / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D050527:Mesangial Cells / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D016212:Transforming Growth Factor beta; D000804:Angiotensin II; D017228:Hepatocyte Growth Factor; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase