SETDB2 mitigates podocyte dysfunction in diabetic kidney disease through epigenetic silencing of SMAD3 [Glomeruli RNA-Seq]

Podocyte dysfunction represents both an early pathological hallmark and a key driver of proteinuria in diabetic kidney disease (DKD); however, the epigenetic mechanisms underlying this process remains poorly defined. Here, we identify the histone methyltransferase SETDB2 as a pivotal epigenetic suppressor of podocyte dysfunction and DKD progression. Glomerular SETDB2 expression is markedly reduced in both DKD patients and mouse models, showing an inverse correlation with disease severity. Podocyte-specific SETDB2 deficiency exacerbates podocytes dysfunction and accelerates DKD progression, whereas its overexpression exerts renal protective effects. Mechanistically, SETDB2 directly enhances H3K9 trimethylation at the Smad3 promoter, thereby repressing SMAD3 expression and activation, ultimately preserving podocyte function. Notably, we identify TCF21, a transcription factor downregulated in DKD, as a direct upstream regulator of Setdb2 expression via promoter binding and transcriptional activation. Collectively, these findings establish SETDB2 as a key regulator of podocyte integrity and a promising therapeutic target for DKD.