Endocytosis mediated by Caveolin-1 inhibits activity of matrix metalloproteinase-2 in human renal proximal tubular cells under hypoxia

Tubulointerstitial fibrosis is characterized by tubular atrophy with basement membrane thickening and accumulation of interstitial extracellular matrix. Decreased matrix metalloproteinase-2 (MMP-2) activity may promote the process. Although human renal proximal tubular cells are sensitive to oxygen deprivation, it is unknown whether cellular endocytosis induced by hypoxia could alter the activity of MMP-2. The aim of this study was to investigate whether the endocytosis mediated by caveolin-1 has inhibitory effects on the activity of MMP-2 in human renal proximal tubular cells (HK-2 cells) under hypoxia. Our study indicated that HK-2 cells exposed to 1% O2 hypoxic milieu for 24 hours resulted in increased level of collagen IV and decreased MMP-2 activity. After HK-2 cells were treated with filipin, the endocytosis mediated by Caveolin-1 was inhibited but the expression of MMP-2 in the cells and its activity in the cultural supernatant was respectively enhanced. Furthermore, inhibition of Caveolin-1 expression by Cav-1 shRNA led to increase of MMP-2 activity, which was similar to the results of HK-2 cells treated with an endocytotic inhibitor filipin under hypoxia. Our data suggest that hypoxia may be an important pro-fibrogenic stimulus that acts partly via endocytosis, and that Caveolin-1 is a potential target for regulating MMP-2 activity in the tubulointerstitial fibrogenesis.