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Hypoxia Activates Src and Promotes Endocytosis Which Decreases MMP-2 Activity and Aggravates Renal Interstitial

Zhengyuan Cheng1, Lei Liu2, Zhi Wang3

  • 1Department of pathology and pathophysiology, Medical School, Southeast University, Dingjiaqiao 87, Gulou district, Nanjing 210009, China. 230159257@seu.edu.cn.

International Journal of Molecular Sciences
|February 22, 2018
PubMed

Insights

Hypoxia in chronic kidney disease decreases matrix metalloproteinase-2 (MMP-2) activity by increasing phospho-Src and Caveolin-1. Inhibiting phospho-Src restores MMP-2 activity, potentially treating renal fibrosis.

Area of Science:

  • Nephrology
  • Cell Biology
  • Molecular Biology

Background:

  • Renal interstitial fibrosis in chronic kidney disease is linked to reduced matrix metalloproteinase-2 (MMP-2) activity.
  • Hypoxia-induced mechanisms regulating MMP-2 activity and fibrosis remain unclear.
  • Caveolin-1 and activated Src (phospho-Src) are implicated in fibrotic pathways.

Purpose of the Study:

  • To elucidate the mechanism by which hypoxia affects MMP-2 activity in renal interstitial fibrosis.
  • To investigate the role of Src and Caveolin-1 in regulating MMP-2 activity under hypoxic conditions.
  • To explore potential therapeutic targets for renal fibrosis.

Main Methods:

  • Established a rat model of renal interstitial fibrosis.
  • Analyzed protein levels of phospho-Src, Caveolin-1, RECK, TIMP-2, and MT1-MMP in kidney tissue and HK-2 cells.
  • Assessed MMP-2 activity in HK-2 cells treated with a phospho-Src inhibitor (PP1) under hypoxia.

Main Results:

  • Hypoxic fibrotic kidney tissue showed increased phospho-Src and Caveolin-1, with decreased MMP-2 activity.
  • PP1 treatment in hypoxic HK-2 cells reduced phospho-Src and Caveolin-1 levels.
  • PP1 treatment enhanced MMP-2 activity and altered levels of MMP-2 regulators (RECK, TIMP-2, MT1-MMP).

Conclusions:

  • Hypoxia promotes Src phosphorylation, which enhances Caveolin-1-mediated endocytosis in HK-2 cells.
  • This process leads to decreased MMP-2 activity, aggravating renal interstitial fibrosis.
  • Targeting phospho-Src may offer a therapeutic strategy for renal fibrosis.
Keywords:
MMP-2 activityendocytosishypoxiarenal interstitial fibrosis

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