Hypoxic tubular epithelial cells regulate the angiogenesis of HMEC-1 cells via mediation of Rab7/MMP-2 axis

Abstract

Renal hypoxia is associated with persisting peritubular capillary rarefaction in progression of chronic kidney disease (CKD), and this phenomenon mainly resulted from the dysregulated angiogenesis. Rab7 is known to be involved in renal hypoxia. However, the mechanism by which Rab7 regulates the renal hypoxia remains unclear. Protein expression was detected by western blot. Cell proliferation was detected by EdU staining. Cell migration was tested by transwell assay. Rab7 was upregulated in HK-2 cells under hypoxia conditions. Hypoxia significantly inhibited the viability and proliferation of human microvascular endothelial cells (HMEC-1 cells), while this phenomenon was obviously reversed by Rab7 silencing. Consistently, Hypoxia significantly decreased the migration and tube length of HMECs, which was partially reversed by knockdown of Rab7. Moreover, hypoxia-induced inhibition of MMP2 activity was significantly rescued by knockdown of Rab7. Moreover, ARP100 (MMP-2 inhibitor) significantly reversed the effect of Rab7 shRNA on cell viability, migration and angiogenesis. Furthermore, knockdown of Rab7 significantly alleviated the fibrosis in tissues of mice. Knockdown of Rab7 significantly alleviated the renal hypoxia in chronic kidney disease through regulation of MMP-2. Thus, our study might shed new light on exploring the new strategies against CKD.

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“…Studies have found that ECs produce VEGF, matrix metallopeptidase 2 (MMP-2), and chemokines to promote neovascularization during acute injury in the lung, liver, and kidney [ 16 , 38 ]. Renal tubular epithelial cells can regulate the angiogenesis function of ECs by upregulating Rab7 gene expression, and mediating the expression of Rab7/MMP-2/VEGF axis [39] . However, when organ damage persists, ECs are aberrantly activated to produce pro-fibrotic mediators such as TGF-β, CCL, and FGF, which induce fibroblast proliferation and production of the ECM [ 16 , 38 , [40] , [41] , [42] ].…”

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“…Before induction of hypoxia in HMEC-1 cells, the medium was replaced with a sugar-free and serum-free medium to simulate nutrient deprivation. In addition, the HMEC-1 cells were placed in a hypoxic chamber (1% O2, 5% CO2, and 94% N2) for further 2 h culture [ 20 ].…”