SETD7 exacerbates diabetic nephropathy through activating A2B receptor-JAK2/STAT3 pathway.

OBJECTIVE: Diabetic nephropathy (DN) is a leading cause of end-stage renal disease (ESRD), and there has been growing attention towards the role of epigenetics in its pathogenesis. This study aims to investigate the underlying mechanism by which SET domain-containing lysine methyltransferase 7 (SETD7) modulates the progression of DN. METHODS: SETD7 knockout mice (Setd7-/-) and wild-type controls (Setd7+/+) were intraperitoneally injected with Streptozocin (STZ, 50 mg/kg) to induce DN. The mouse mesangial cell line SV40-MES-13 were stimulated by high glucose in vitro. RESULTS: SETD7 expression was predominantly upregulated in high glucose-induced glomerular mesangial cells (MCs), and in diabetic mice kidney. Notably, SETD7 promoted the transcription of adenosine A2B receptor (A2BR), which mediated the activation and phosphorylation of JAK2 (p-JAK2) via direct interaction. Subsequently, p-JAK2 facilitated the recruitment of signal transducer and activator of transcription 3 (STAT3) to binding sites. This led to nuclear translocation of STAT3 and transcriptional regulation of target genes, ultimately promoting fibrosis and inflammation. Importantly, SETD7 deficiency reduced A2BR transcription, thereby inhibiting fibrosis and inflammation in high glucose-induced MCs. Consistently with these findings, SETD7 knockout in STZ-induced mice conferred significant protection against renal injury and reduced glomerular fibrosis. CONCLUSIONS: Our results demonstrate an important role and mechanism of SETD7 in DN by promoting fibrosis and inflammation through the A2BR-mediated JAK2/STAT3 signaling pathway. Targeting SETD7 may represent a promising therapeutic strategy for halting the progression of DN.