Abstract / Summary
Diabetic kidney disease (DKD) is the predominant cause of end-stage kidney disease, with podocyte injury being a key factor in DKD. Research has shown that RNA demethylase fat-mass and obesity-associated protein (FTO) is related to podocyte injury. In prior research, we modulated FTO in podocytes and conducted MeRIP-seq and RNA-seq, through which early growth response 1 (EGR1) was identified. Nonetheless, the precise role of EGR1 in DKD remains to be elucidated. Here, we demonstrated that FTO was critical in podocyte injury, enhancing EGR1 mRNA stability in an m6A-YTHDF2 dependent manner. EGR1 was elevated in podocytes from individuals with DKD, and associated with eGFR and 24 h urinary protein. In vitro , high glucose stimulated EGR1 expression in cultured human podocytes. Silencing EGR1 mitigated the injury and inflammation in podocytes caused by high glucose, whereas its overexpression exacerbated the damage. Mechanistically, EGR1 binds to the STING1 promoter to enhance its transcription, which in turn activates the STING1/TBK1/NF-κB signaling cascade, thereby driving podocyte inflammatory injury. In vivo , podocyte-specific deletion of EGR1 significantly attenuated podocyte and glomerular damage in streptozotocin-induced diabetic mice fed a high-fat diet. Conversely, podocyte-specific EGR1 upregulation worsened podocyte damage and proteinuria in these diabetic mice. In summary, EGR1 played a vital role in DKD podocyte injury, and could be a prospective new treatment strategy for DKD.