Hepatocyte growth factor attenuates renal fibrosis through TGF-β1 suppression by apoptosis of myofibroblasts

Iekushi, Kazuma; Taniyama, Yoshiaki; Azuma, Junya; Sanada, Fumihiro; Kusunoki, Hiroshi; Yokoi, Taishi; Koibuchi, Nobutaka; Okayama, Kiyohiko; Rakugi, Hiromi; Morishita, Ryuichi

doi:10.1097/hjh.0b013e32833e4149

Cited by 57 publications

(49 citation statements)

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“…17 In addition, our recent study demonstrated that HGF induced apoptosis of myofibroblasts, associated with an increase in MMPs expression and a decrease in ECM, potentially because of inhibition of TGF-␤1 signaling. 5,18,19 In addition to these known mechanisms, the present study suggests a novel pathway through the PI3K-Akt/PTEN pathway. HGF plays the role of antiapoptotic effect, mediating the activation of Akt/ PI3K pathway.…”

Section: Discussionmentioning

confidence: 61%

“…5 As shown in Figure S1 (available in the online Data Supplement), TGF-␤1 significantly stimulated the expression of AT 1 R mRNA in a time-dependent manner from 1 to 24 hours (PϽ0.01). In contrast, Ang II stimulation alone did not change AT 1 R mRNA expression ( Figure 1A).…”

Section: Role Of Phosphatase and Tensin Homolog Deleted On Chromosommentioning

confidence: 85%

“…21,22 On the other hand, HGF induced apoptotic cell death in some distinct types of cells, including transformed or neoplastic cells 23 and myofibroblasts. 5,18,19 It might be a reason that HGF biologically regulates cell survival in a cell type-dependent manner. Furthermore, our recent study reported that HGF promotes oxidative stress in cultured endothelial cells but inhibits Ang II-induced excess oxidative stress thorough an epidermal growth factor receptor degradation mechanism.…”

Section: Discussionmentioning

confidence: 99%

“…In contrast, renal AT 1 R mRNA induced by Ang II infusion was significantly lower in HGF-Tg mice ( Figure 4A; PϽ0.05). Because our previous report demonstrated that TGF-␤1 mRNA expression was significantly lower in HGF-Tg mice as compared with control, 5 we hypothesized that HGF might affect PTEN expression and Akt phosphorylation in the kidney, because PTEN attenuated Akt phosphorylation. As shown in Figure 4B, Ang II infusion to control mice induced a marked decrease in the level of PTEN and an increase in the level of Akt phosphorylation.…”

Section: Overexpression Of Hgf Inhibited Renal Damage Induced By Ang mentioning

confidence: 96%

“…4 In addition, our group demonstrated recently that HGF promoted apoptosis of myofibroblasts, an important source of TGF-␤1. 5 However, the molecular mechanisms of inhibition of the Ang II-TGF␤ pathway by HGF have not been fully clarified. Thus, in this study, we investigated how HGF counteracts the positive feedback loop between Ang II and TGF-␤1 that results in amplification of their profibrotic effects in the kidney.…”

mentioning

confidence: 99%

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Hepatocyte Growth Factor Attenuates Transforming Growth Factor-β-Angiotensin II Crosstalk Through Inhibition of the PTEN/Akt Pathway

et al. 2011

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Abstract-Both angiotensin II (Ang II) and transforming growth factor (TGF)-␤1 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-␤1. Therefore, in this study, we investigated the molecular mechanisms of how HGF antagonizes the Ang II-TGF-␤ axis in renal cells. In cultured human mesangial cells, TGF-␤1 increased angiotensin type 1 receptor (AT 1 R) mRNA, mainly dependent on the Akt/phosphatidylinositol 3-kinase signaling pathway. Furthermore, TGF-␤1 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-␤ pathway, because Ang II increased TGF-␤ expression. In contrast, HGF significantly attenuated the increase in AT 1 R gene expression, and inhibited the decrease in PTEN induced by TGF-␤1. Of importance, a PTEN-specific inhibitor significantly attenuated the reduction in TGF-␤1-induced AT 1 R expression by HGF. These data suggest that HGF attenuated TGF-␤1-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-␤1-AT 1 R, mediating the inhibition of PTEN.

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