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

Int J Mol Sci

Department of pathology and pathophysiology, Medical School, Southeast University, Dingjiaqiao 87, Gulou district, Nanjing 210009, China.

Published: February 2018

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.

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5855803PMC
http://dx.doi.org/10.3390/ijms19020581DOI Listing

Publication Analysis

Top Keywords

mmp-2 activity
28
renal interstitial
16
interstitial fibrosis
16
hk-2 cells
16
increased mmp-2
12
protein levels
12
activity aggravates
8
aggravates renal
8
activity hypoxic
8
hypoxic hk-2
8

Similar Publications

Vitamin Bs as Potent Anticancer Agents through MMP-2/9 Regulation.

Front Biosci (Landmark Ed)

January 2025

Department of Chemistry Education, Kongju National University, 32588 Gongju, Chungcheongnam-do, Republic of Korea.

In recent years, the role of coenzymes, particularly those from the vitamin B group in modulating the activity of metalloenzymes has garnered significant attention in cancer treatment strategies. Metalloenzymes play pivotal roles in various cellular processes, including DNA repair, cell signaling, and metabolism, making them promising targets for cancer therapy. This review explores the complex interplay between coenzymes, specifically vitamin Bs, and metalloenzymes in cancer pathogenesis and treatment.

View Article and Find Full Text PDF

Sepsis is a clinical condition causing tissue damage as a result of infection and an exaggerated immune response. Sepsis causes 11 million deaths annually, a third of which are associated with acute lung injury (ALI). Rapid and effective treatment is crucial to improve survival rates.

View Article and Find Full Text PDF

Irisin is a newly discovered 12 kDa messenger protein involved in energy metabolism. Irisin affects signaling pathways in several types of cancer; however, the role of irisin in metastatic melanoma (MM) has not been described yet. We explored the biological effects of irisin in in vitro models of MM cells (HBL, LND1, Hmel1 and M3) capable of the oncogenic activation of BRAF.

View Article and Find Full Text PDF

Non-small-cell lung cancer (NSCLC) remains the leading cause of cancer-related deaths globally, with a persistently low five-year survival rate of only 14-17%. High rates of metastasis contribute significantly to the poor prognosis of NSCLC, in which inflammation plays an important role by enhancing tumor growth, angiogenesis, and metastasis. Targeting inflammatory pathways within cancer cells may thus represent a promising strategy for inhibiting NSCLC metastasis.

View Article and Find Full Text PDF

Colorectal cancer (CRC) remains one of the most prevalent and lethal cancers worldwide, prompting ongoing research into innovative therapeutic strategies. This review aims to systematically evaluate the role of gelatinases, specifically MMP-2 and MMP-9, as therapeutic targets in CRC, providing a critical analysis of their potential to improve patient outcomes. Gelatinases, specifically MMP-2 and MMP-9, play critical roles in the processes of tumor growth, invasion, and metastasis.

View Article and Find Full Text PDF

Want AI Summaries of new PubMed Abstracts delivered to your In-box?

Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!