ZBP1 Mediates Renal Tubular Injury in Diabetic Nephropathy Through RIPK3-mediated Necroptosis

Diabetic nephropathy (DN) is the leading cause of end-stage renal disease. Given the limited therapeutic options, identifying novel differentially expressed genes and therapeutic targets is crucial for DN. We performed transcriptome sequencing of kidney tissue from DN patients and applied bioinformatics analyses to identify dysregulated pathways and candidate genes. Transcriptomic analysis revealed significant enrichment of the necroptosis pathway in DN kidney tissues, with Z-DNA binding protein 1 (ZBP1) showing the most pronounced differential expression among pathway-associated genes. Clinical and pathological data were collected from DN patients to evaluate the correlation between ZBP1 expression and key indicators of renal function and injury, thereby assessing its association with DN progression. Our results indicate that ZBP1 expression was significantly upregulated in DN kidney tissues compared to normal peritumour tissue, and correlated with renal tubule injury and renal function. Functional studies demonstrated that ZBP1 knockdown attenuated necroptosis, tubular injury, inflammation, and fibrosis in both db/db mice and high glucose/advanced glycation end products (HG/AGEs)-stimulated MTECs (mouse renal tubular epithelial cells). Mechanistically, ZBP1 directly interacts with receptor interacting protein kinase 3 (RIPK3) to promote necroptotic cell death. Furthermore, we identified ETS proto-oncogene 1 (ETS1) as a transcriptional activator of ZBP1 under HG conditions. In summary, this study identifies ZBP1 as a key mediator of tubular injury, inflammation and fibrosis in DN via RIPK3-dependent necroptosis, highlighting its potential as a therapeutic target.