Tet1 deficiency exacerbates oxidative stress in acute kidney injury by regulating superoxide dismutase

Abstract

<b>Rationale:</b> Increased methylation of key genes has been observed in kidney diseases, suggesting that the ten-eleven translocation (Tet) methyl-cytosine dioxygenase family as well as 5mC oxidation may play important roles. As a member of the Tet family, the role of Tet1 in acute kidney injury (AKI) remains unclear. <b>Methods:</b> <i>Tet1</i> knockout mice, with or without tempol treatment, a scavenger of reactive oxygen species (ROS), were challenged with ischemia and reperfusion (I/R) injury or unilateral ureteral obstruction (UUO) injury. RNA-sequencing, Western blotting, qRT-PCR, bisulfite sequencing, chromatin immunoprecipitation, immunohistochemical staining, and dot blot assays were performed. <b>Results:</b> Tet1 expression was rapidly upregulated following I/R or UUO injury. Moreover, <i>Tet1</i> knockout mice showed increased renal injury and renal cell death, increased ROS accumulation, G2/M cell cycle arrest, inflammation, and fibrosis. Severe renal damage in injured <i>Tet1</i> knockout mice was alleviated by tempol treatment. Mechanistically, Tet1 reduced the 5mC levels in an enzymatic activity-dependent manner on the promoters of <i>Sod1</i> and <i>Sod2</i> to promote their expression, thus lowering injury-induced excessive ROS and reducing I/R or UUO injury. <b>Conclusions:</b> Tet1 plays an important role in the development of AKI by promoting SOD expression through a DNA demethylase-dependent mechanism.