SETDB2 Mitigates Podocyte Dysfunction in Diabetic Kidney Disease Through Epigenetic Silencing of SMAD3.

ABSTRACT: Podocyte dysfunction represents both an early pathological hallmark and a key driver of proteinuria in diabetic kidney disease (DKD); nevertheless, the potential epigenetic regulatory mechanisms remain poorly defined. Here, the histone methyltransferase SETDB2 is identified as a pivotal epigenetic suppressor of podocyte dysfunction and DKD progression. Glomerular SETDB2 expression exhibits a significant reduce 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 activ

SUBMITTER: Li L 

PROVIDER: S-EPMC12904062 | biostudies-literature | 2026 Feb

REPOSITORIES: biostudies-literature