Tet2通过去甲基化Fgf1启动子来缓解急性肾损伤。

Abstract

Acute kidney injury (AKI) is characterized by a sudden deterioration of renal function, tubular epithelial cell (TEC) damage, and inflammatory responses, yet effective therapies are limited. In this study, we found that Tet methylcytosine dioxygenase 2 ( Tet2 ) expression and global genomic 5-hydroxymethylcytosine (5hmC) levels are significantly decreased in both patients and mice with AKI. Conditional deletion of Tet2 in TECs exacerbated kidney dysfunction and renal inflammation. In vitro experiments demonstrated that Tet2 knockdown aggravated cellular injury and inflammatory responses, whereas its overexpression alleviated these effects. Mechanistically, integrated analyses of whole-genome bisulphite sequencing and RNA sequencing revealed that Tet2 enhances Fgf1 transcription through promoter 5hmC modification, thereby reducing renal injury and inflammation. Furthermore, high-dose ascorbic acid, a pharmacological activator of TET2, exerted significant reno-protective effects. Overall, both genetic and pharmacological targeting of TET2 restored 5hmC levels at the Fgf1 promoter and attenuated the severity of AKI, highlighting the Tet2 /5hmC/ Fgf1 axis as a promising therapeutic target for AKI. TET2-mediated 5hmC at the Fgf1 promoter upregulates FGF1 to alleviate renal inflammation and injury, while high-dose ascorbic acid enhances TET2 activity to drive this process. Download: Download high-res image (182KB) Download: Download full-size image