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NSD2 Drives Podocyte Injury in Diabetic Kidney Disease via Epigenetic Regulation of Hippo Signaling [RNA-Seq]

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE313713 | GEO | 2026/02/01

REPOSITORIES: GEO

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Project description:Diabetic kidney disease, a major microvascular complication of diabetes, is the primary cause of end-stage renal disease globally 1. Current treatments mainly target glycemic, blood pressure, and lipid control but often fail to prevent renal impairment. Early DKD is characterized by tubular damage, glomerular hypertrophy, thickening of the glomerular basement membrane, and loss of podocytes. Podocyte damage and loss are potentially significant in the pathogenesis of DKD. Hyperglycemia, a critical factor in podocyte injury, can contribute to the progression of DKD. Therefore, mitigating podocyte injury may be a crucial factor in the future management and alleviation of DKD. Chronic hyperglycemia leads to podocyte dysfunction through inflammation, oxidative stress, autophagy, and apoptosis. As is well known, the non-enzymatic glycation of proteins, leading to the formation of advanced glycation end-products (AGEs), constitutes a significant contributing factor to DKD. Notably, recent studies underscore the crucial role of O-linked-N-acetylglucosamine (O-GlcNAc) modification (also known as O-GlcNAcylation) in DKD progression. The hexosamine biosynthesis pathway (HBP) converts glucose to UDP-N -acetylglucosamine (UDP-GlcNAc), a substrate for O-GlcNAcylation, which is catalyzed by O-GlcNAc transferase (OGT) and removed by O-GlcNAcase (OGA). Aberrant O-GlcNAcylation is linked to renal fibrosis, inflammation, and apoptosis, which worsen diabetic kidney function. Elevated levels of O-GlcNAcylation have been observed in renal tissues of diabetic patients, indicating a potential link between hyperglycemia and dysregulated O-GlcNAc signaling. However, the exact molecular mechanisms of O-GlcNAcylation in DKD are not well understood. This study explores the changes in protein and glycosylated protein in podocytes after OGT knockdown to learn the molecular mechanisms of podocyte injury induced by high glucose (HG). A total of 128 up-regulated proteins and 45 down-regulated proteins in OGT knockdown group than in the control group were identified. Furthermore, 55 significantly changed glycosylation modification sites on 43 proteins were identified. To the best of our knowledge, this is the first study to conduct a global analysis of O-GlcNAcylation in podocytes.

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NSD2 Drives Podocyte Injury in Diabetic Kidney Disease via Epigenetic Regulation of Hippo Signaling [RNA-Seq]

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