Aim To explore the effect and significance of mammalian sterile 20-like kinase 1 (MST1) and its DNA methylation in the kidney damage of apolipoprotein E gene knocked-out (ApoE－/－) mice. Methods The experimental animals were divided into 2 groups:(1)ApoE－/－ group (n＝10):male ApoE－/－ mice were fed with high methionine diet; (2)Control group (n＝10):male C57BL/6J mice were fed with high methionine diet. After 14 weeks of feeding, serum creatinine and urea nitrogen levels in mice were determined by full automatic biochemical analyzer. PAS staining and transmission electron microscope were used to observe the renal tissue damage in mice. Real-time quantitative PCR and Western blot were used to detect the expression levels of MST1 mRNA and protein in mice kidney. MST1 DNA methylation level in mice kidney was detected by nested methylation specific PCR (nMS-PCR). Results Compared with the control group, serum levels of creatinine and urea nitrogen were increased by 1.1 times and 1.6 times in ApoE－/－ group (P＜0.01). PAS staining and transmission electron microscopy showed that the kidney was obviously damaged in ApoE－/－ group compared with control group. In ApoE－/－ mouse kidney, MST1 expression was positively correlated with serum creatinine and urea nitrogen levels (R²＝0.7571, P＝0.0012; R²＝0.7342, P＝0.0015). The result of nMS-PCR showed that renal MST1 DNA methylation level in ApoE－/－ group was significantly lower than that in control group (P＜0.01). Conclusions The upregulation of MST1 expression may play an important role in kidney damage of ApoE－/－ mice. DNA low methylation in MST1 promoter region may be an important mechanism of MST1 expression upregulation.