Aim To investigate whether angiotensin(1-7) [Ang(1-7)]/Mas receptor axis protects human umbilical vein endothelial cells (HUVEC) against high glucose (HG)-induced injury by modulating ATP-sensitive K＋ channels (KATP channels). Methods Human umbilical vein endothelial cells were exposed to 40 mmol/L glucose to establish a model of HG-induced insults. The expression level of KATP channel protein was determined by Western blot, CCK-8 assay was used to test the cell viability, lactate dehydrogenase (LDH) activity in the culture medium was measured with commercial kits, Hoechst33258 staining was used to assess the number of apoptotic cells followed by photofluorography, the intracellular generation of reactive oxygen species (ROS) was measured by 2′, 7′-dichlorfluorescein-diacetate (DCFH-DA) staining followed by photofluorography, mitochondrial membrane potential (MMP) was detected by Rhodamine123 staining followed by photofluorography, the secretion levels of interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) were detected by ELISA. Results Human umbilical vein endothelial cells were treated with 40 mmol/L glucose for 1～24 h, respectively. After human umbilical vein endothelial cells were exposed to HG for 3 h, the level of KATP channel protein decreased in a time-dependent manner, reaching the maximum decrease at the 24 h point. Co-treatment of the cells with 20 μmol/L Ang(1-7) and HG for 24 h ameliorated the down-regulation of KATP channel protein induced by HG.In addition, co-treatment of the cells with 20 μmol/L Ang(1-7) and HG or pre-treatment of the cells with 100 μmol/L pinacidil (a KATP channel opener) antagonized HG-induced injuries, evidenced by an increase in cell viability, a decrease in the activity of LDH, apoptotic cell number, ROS generation, MMP loss as well as the secretion levels of IL-1β and TNF-α. Co-treatment with 10 μmol/L A-779 (an inhibitor of Mas receptor) and HG or pre-treatment or 1 mmol/L glibenclamide (a KATP channel blocker) attenuated the above protective effects of Ang(1-7). Conclusion Ang(1-7)/Mas receptor axis protects human umbilical vein endothelial cells against HG-induced injury by modulating KATP channels.