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Hepatocyte growth factor attenuates transforming growth factor-β-angiotensin II crosstalk through inhibition of the PTEN/Akt pathway. | LitMetric

AI Article Synopsis

  • Both angiotensin II (Ang II) and TGF-β1 contribute to the worsening of chronic kidney disease, while hepatocyte growth factor (HGF) plays a protective role by counteracting these effects.
  • The study found that TGF-β1 increases angiotensin type 1 receptor (AT(1)R) expression by affecting specific signaling pathways, while HGF inhibits this increase and promotes the activity of PTEN, a regulator that controls these pathways.
  • In experiments with mice genetically modified to produce more HGF, researchers observed reduced kidney damage and fibrosis, suggesting HGF can disrupt the harmful Ang II-TGF-β1 cycle, particularly by enhancing PTEN levels.

Article 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.

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Source
http://dx.doi.org/10.1161/HYPERTENSIONAHA.111.173013DOI Listing

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