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DJ-1 alleviates high glucose-induced podocyte injury via activating ERK1/2 signaling

ABSTRACT: Diabetic nephropathy (DN) is one of the most common complications of diabetes. DJ-1 has been reported to participate in the response to renal ischemia/reperfusion (I/R) injury. However, the underlying mechanisms of DJ-1 in the regulation of high glucose-induced renal injury remain obscure. In this study, we performed RNA-seq to explore the function of high glucose on human podocyte cells (HPC), and found that high glucose widely regulated a variety of signaling pathways, including cell growth and death, signal transduction, etc. Furthermore, we found that DJ-1 was decreased in the high glucose conditions and DJ-1 could attenuate the high glucose-induced HPC apoptosis. Mechanically, overexpression of DJ-1 increased the phosphorylation of ERK1/2 (p-ERK1/2) and then mediated the transport of p-ERK1/2 from the cytoplasm to the nucleus. Furthermore, the accumulation of p-ERK1/2 in the nucleus activated the ERK1/2 pathway and enhanced the expression of NF-κB p65 and AP-1, which inhibited the apoptosis of HPC in the high glucose milieu. In conclusion, our study demonstrated that high glucose decreased DJ-1 expression in HPC and that overexpression of DJ-1 attenuated the apoptosis of HPC in high glucose conditions via enhancing the ERK1/2 pathway and the expression of NF-κB p65 and AP-1. Our study provides a novel mechanism by which DJ-1 alleviates high glucose-induced podocyte injury.

ORGANISM(S): Homo sapiens

PROVIDER: GSE307956 | GEO | 2026/04/22

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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DJ-1 alleviates high glucose-induced podocyte injury via activating ERK1/2 signaling

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