Objective To study the role of high lipid-mediated endoplasmic reticulum stress in human glomerular mesangial cells (HMCs) injury under inflammation condition, and to explore the mechanism of lipid-induced kidney injury.Methods HMCs were divided into control group, high lipid group, inflammatory stress group, high lipid plus inflammatory stress group, and high lipid plus inflammatory stress plus 4-phenylbutyric acid (4-PBA) group. After culture for 24 h, 48 h, and 72 h, Oil red O staining was used to evaluate lipid droplet accumulation in the cells; cell proliferation was assessed by MTT assay; expression of GRP78 protein was measured by immunocytochemistry method; and the levels of GRP78 and FN mRNA were examined by real-time PCR.Results (1) Compared with control group, the high lipid group, inflammatory stress group and high lipid plus inflammatory stress group had significantly increased intracellular cholesterol levels (all P<0.01), significantly higher FN mRNA levels (all P<0.01), and significantly faster cell proliferation (all P<0.01), which was in a time-dependent manner. Compared with high lipid plus inflammatory stress group, 4-PBA group had significantly reduced lipid deposition (all P<0.01), slower cell proliferation (all P<0.01) and lower FN mRNA expression (P<0.05, P<0.01) induced by high lipid. (2) Compared with control group, high lipid group, inflammatory group and high lipid plus inflammatory stress group had significantly increased expression of GRP78 mRNA and protein (P<0.05,P<0.01), and the expression in 4-PBA treatment group was significantly lower than that in the high lipid plus inflammatory stress group (all P<0.01). (3) After treatment with high lipid or inflammation for 24 h, 48 h and 72 h, the intracellular cholesterol level was positively correlated with mesangial cell proliferation and expression of GRP78 protein and FN mRNA (all P<0.01). The cellular expression of GRP78 protein was positively correlated with mesangial cell proliferation and FN mRNA expression (all P<0.05). Conclusion High lipid can induce glomerular mesangial cell injury through activating endoplasmic reticulum stress in HMCs under inflammation stress condition.