There is increasing evidence that mesangial cells are important targets of chronic hypoxia injury. Impaired Ca2+ signaling has been found in mesangial cells (MCs) subjected to chronic hypoxia. However, the mechanisms underlying this phenomenon have not yet been defined. In the present study, we found that chronic hypoxia enhanced the expression of TRPC6 and TRPC6-dependent Ca2+ entry, and TRPC6 knockdown inhibited the chronic hypoxia-induced increase in [Ca2+]i, suggesting that TRPC6-mediated Ca2+ entry is responsible for the elevated [Ca2+]i induced by chronic hypoxia in MCs. In addition, TRPC6 knockdown attenuated chronic hypoxia-induced actin assembly and actin reorganization. We concluded that the upregulation of TRPC6 is involved in the Ca2+ signaling and actin assembly in human MCs after chronic hypoxia. These findings provide new insight into the mechanisms underlying the cellular response of MCs to hypoxia. (C) 2012 Elsevier Inc. All rights reserved.