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Int. J. Mol. Sci. 2018, 19(2), 581; https://doi.org/10.3390/ijms19020581

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

Department of Pathology and Pathophysiology, Medical School, Southeast University, Dingjiaqiao 87, Gulou District, Nanjing 210009, China
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Received: 21 December 2017 / Revised: 22 January 2018 / Accepted: 12 February 2018 / Published: 15 February 2018
(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)
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Abstract

The aggravation of renal interstitial fibrosis in the advanced-stage of chronic kidney disease is related to decreased matrix metalloproteinase-2 (MMP-2) activity, which is induced by hypoxia in the kidney; however, the specific mechanism remains unclear. We previously demonstrated that inhibition of Caveolin-1, a key gene involved in endocytosis, increased MMP-2 activity in hypoxic HK-2 cells. It has been reported that activated Src (phospho-Src Tyr416) is a key molecule in multiple fibrotic pathways. However, whether Src functions on the regulation of Caveolin-1 and MMP-2 activity in hypoxic HK-2 cells remains poorly understood. To explore the underlying mechanism, a rat model of renal interstitial fibrosis was established, then we observed obvious hypoxia in fibrotic kidney tissue and the protein levels of phospho-Src and Caveolin-1 increased, while MMP-2 activity decreased. Next, we treated HK-2 cells with the phospho-Src inhibitor PP1. Compared with normal cells grown in hypoxia, in cells treated with PP1, the protein levels of phospho-Src and Caveolin-1 decreased, as did the protein levels of the MMP-2-activity-regulated molecules RECK (reversion-inducing-cysteine-rich protein with kazal motifs) and TIMP-2 (tissue inhibitor of metalloproteinase-2), while the protein level of MT1-MMP (membrane type 1-matrix metalloproteinase) increased and MMP-2 activity was enhanced. Therefore, hypoxia promotes the phosphorylation of Src and phospho-Src can enhance the endocytosis of HK-2 cells, which leads to decreased MMP-2 activity and aggravates renal interstitial fibrosis. View Full-Text
Keywords: renal interstitial fibrosis; hypoxia; endocytosis; MMP-2 activity renal interstitial fibrosis; hypoxia; endocytosis; MMP-2 activity
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).
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Cheng, Z.; Liu, L.; Wang, Z.; Cai, Y.; Xu, Q.; Chen, P. Hypoxia Activates Src and Promotes Endocytosis Which Decreases MMP-2 Activity and Aggravates Renal Interstitial Fibrosis. Int. J. Mol. Sci. 2018, 19, 581.

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