Aim: To explore the effect of the DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine (Aza) on early renal injury. Materials & methods: Cell damage and inflammation are features of early renal injury. The apoptosis and inflammation in hypoxia/reoxygenation (H/R)-induced human proximal tubular epithelial cells (HK-2) and ischemia-reperfusion kidney were studied, and expression of the protein klotho was investigated. Results: Aza induced HK-2 apoptosis in a dose-dependent manner, but low-dose Aza attenuated the apoptosis and inflammation in H/R-induced HK-2 cells and ischemia-reperfusion kidney. Low-dose Aza ameliorated renal function in mice with renal ischemia-reperfusion injury. Meanwhile, low-dose Aza upregulated klotho expression in H/R-induced HK-2 cells and ischemia-reperfusion kidney. Klotho knockdown abrogated the effects of low-dose Aza on apoptosis and inflammation. Conclusion: Low-dose Aza protects against renal early injury by increasing klotho expression.
Keywords: 5-aza-2′-deoxycytidine; DNA methyltransferase; apoptosis; inflammation; klotho; renal.
DNA methylation affects kidney disease and might be a clinically useful therapeutic target for kidney disease. It has been reported that blocking DNA methylation may reduce renal fibrosis. Early renal injury is a priming event of late renal function failure, and inhibition of early renal injury may be beneficial to prevent late loss of function. In this study, the DNA methyltransferase inhibitor 5-aza-2′-deoxycytidine was studied for its effects on cell apoptosis and inflammation in early renal injury. Low-dose 5-aza-2′-deoxycytidine had antiapoptotic and anti-inflammatory effects on HK-2 cells induced by hypoxia/reoxygenation and renal tissue with ischemia–reperfusion injury (IRI), and improved renal function following renal IRI. Possible mechanisms involved reduced methylation of klotho promoter DNA and upregulation of klotho expression. Therefore, it is attractive to speculate that preventing DNA methylation may be an effective strategy or method to attenuate renal early injury or renal IRI in human patients, as it is in rodents.