NSD2 Drives Podocyte Injury in Diabetic Kidney Disease via Epigenetic Regulation of Hippo Signaling

Podocyte lipid accumulation has emerged as an important driver during the progression of diabetic kidney disease (DKD), yet the underlying mechanisms remain not fully clarified. Here, we identified the histone methyltransferase NSD2 as a key epigenetic regulator of podocyte lipid accumulation and injury in DKD. NSD2 expression is markedly increased in podocytes from both DKD patients and mouse models, and its levels shows a positive correlation with disease severity. Genetic deletion of Nsd2 in podocytes, as well as pharmacological inhibition of its methyltransferase activity, substantially reduced podocyte injury and proteinuria in mouse models. In contrast, transgenic Nsd2 overexpression in podocytes aggravated these pathological alterations. Mechanistically, elevated NSD2 in DKD enhances H3K36me2 deposition at the Ajuba promoter, resulting in its transcriptional upregulation and subsequent suppression of Hippo signaling. This epigenetic change promotes lipid accumulation in podocytes, leading to cytoskeletal disturbances and increased apoptosis. Collectively, our findings reinforce lipid accumulation as a central contributor to DKD progression and indicate that NSD2, as a pivotal epigenetic regulator in this process, could represent a reasonable therapeutic target for DKD. Overall design: Comparative gene expression profiling analysis of RNA-seq data from kidneys and isolated glomeruli of 24-week HFD/STZ-induced diabetic mice and control mice.