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Hepatocyte growth factor suppresses transforming growth factor-beta-1 and type III collagen in human primary renal
Shan Mou1, Qin Wang, Beili Shi
1Renal Division, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
Abstract:
Tubulointerstitial changes in the diabetic kidney correlate closely with renal fibrosis, and transforming growth factor-beta-1 (TGF-beta1) is thought to play a key role in this process. In contrast, hepatocyte growth factor (HGF) has shown therapeutic effects on injured renal tubules in animal models. This study was undertaken to test the hypothesis that the preventive effects of HGF may result from interventions in TGF-beta1-mediated signaling and collagen III secretion. We examined the expression of HGF/HGF receptor (c-Met) and TGF-beta1 in renal fibroblasts at multiple time points. The effects of recombinant human HGF on TGF-beta1 expression were studied by RT-PCR and Western blotting, and the levels of collagen III were measured by ELISA. In the high-glucose condition, the expression of HGF and c-Met in renal fibroblasts was detected as early as 6 hours following cell culture while the level of TGF-beta1 peaked at 96 hours. The addition of recombinant human HGF to the culture media dose-dependently inhibited TGF-beta1 mRNA expression and reduced collagen III secretion by 34%. These results indicate that, during hyperglycemia, HGF inhibits TGF-beta1 signaling and type III collagen activation in interstitial fibroblasts. Furthermore, we should recognize that changes in the balance between HGF and TGF-beta1 might be decisive in the pathogenesis of chronic renal fibrosis. Therefore, administration of HGF to restore this balance may offer a novel therapeutic intervention in managing renal fibrogenesis in diabetic nephropathy.
Insights
Hepatocyte growth factor (HGF) may prevent diabetic kidney fibrosis by inhibiting transforming growth factor-beta-1 (TGF-beta1) signaling. HGF administration could be a novel therapeutic approach for diabetic nephropathy.
Area of Science:
- Nephrology
- Cell Biology
- Molecular Medicine
Background:
- Diabetic kidney disease is characterized by tubulointerstitial changes and renal fibrosis.
- Transforming growth factor-beta-1 (TGF-beta1) is implicated in diabetic kidney fibrosis.
- Hepatocyte growth factor (HGF) has demonstrated therapeutic potential in animal models of kidney injury.
Purpose of the Study:
- To investigate if HGF's preventive effects on diabetic kidney fibrosis involve modulating TGF-beta1 signaling and collagen III secretion.
- To examine the expression dynamics of HGF/c-Met and TGF-beta1 in renal fibroblasts under high-glucose conditions.
- To determine the impact of recombinant human HGF on TGF-beta1 expression and collagen III production.
Main Methods:
- Cultured human renal fibroblasts under high-glucose conditions.
- Assessed HGF, c-Met, and TGF-beta1 expression using RT-PCR and Western blotting.
- Quantified collagen III levels via ELISA.
- Administered recombinant human HGF to evaluate dose-dependent effects.
Main Results:
- HGF and c-Met expression were detected in renal fibroblasts within 6 hours of high-glucose exposure.
- TGF-beta1 levels peaked at 96 hours under high-glucose conditions.
- Recombinant human HGF significantly inhibited TGF-beta1 mRNA expression and reduced collagen III secretion by 34% in a dose-dependent manner.
Conclusions:
- HGF inhibits TGF-beta1 signaling and type III collagen activation in renal fibroblasts during hyperglycemia.
- The balance between HGF and TGF-beta1 is crucial in the pathogenesis of chronic renal fibrosis.
- HGF administration represents a potential therapeutic strategy for managing renal fibrogenesis in diabetic nephropathy.
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