The Mechanism of S-adenosylhomocysteine Hydrolase in Regulating Podocyte Apoptosis and Diabetic Nephropathy via Moap1.

Elevated levels of S-adenosylhomocysteine (SAH) in patients with diabetes are closely associated with renal dysfunction. Inhibition of SAH hydrolase (SAHH) increases SAH levels, promotes apoptosis, and exacerbates streptozotocin (STZ)-induced diabetic nephropathy. However, the precise mechanism by which SAHH inhibition induces podocyte apoptosis remains unclear. This study aimed to investigate how SAHH inhibition specifically induces podocyte apoptosis and to elucidate the underlying molecular mechanisms. We established an STZ-induced podocyte-specific SAHH knockout mouse model and an in vitro model of high-glucose-treated podocytes. Our results showed that podocyte-specific SAHH deletion significantly exacerbated streptozotocin (STZ)-induced diabetic kidney injury. SAHH inhibition significantly upregulated the expression of modulator of apoptosis 1 (Moap1), which in turn promoted podocyte apoptosis through activation of the pro-apoptotic protein BAX. Knockdown of Moap1 partially reversed this apoptotic phenotype. Mechanistically, SAHH inhibition downregulated DNA methyltransferase 3b (DNMT3b) expression, leading to hypomethylation of the Moap1 promoter and subsequent upregulation of Moap1 transcription. ChIP-qPCR and dual-luciferase reporter assays confirmed that DNMT3b directly bound to the region of the Moap1 promoter and regulated its transcriptional activity. Restoration of DNMT3b expression reversed Moap1 upregulation and partially rescued the apoptotic phenotype induced by SAHH inhibition. Collectively, these findings demonstrate that SAHH inhibition promotes podocyte apoptosis by upregulating Moap1 expression through a DNMT3b-dependent hypomethylation mechanism, which in turn activates BAX. This study provides novel potential therapeutic targets for diabetic nephropathy with elevated SAH levels.