Background and aims: Circulating levels of neuroblastoma suppressor of tumorigenicity 1 (NBL1) are predictive of developing end stage kidney disease (ESKD) in cohorts of patients with either type 1 or type 2 diabetes. NBL1 abundance positively correlates with podocyte loss because it causes podocyte death. The aim of our study was to develop NBL1 blocking agents and test whether they could prevent podocyte death in vitro and delay diabetic kidney disease (DKD) onset in vivo. Materials and methods: We screened a library of anti-NBL1 antibodies by using an in vitro cell death assay, which measured NBL1-induced apoptosis of human immortalized podocytes. Stem cell-derived human kidney organoids were used for further screening. Selected candidates were administered to streptozotocin (STZ)-induced diabetic mice as well as leptin receptor deficient mice (Db/Db) and renal damage was assessed by quantifying mesangial expansion, expression of pro-fibrotic and pro-death markers and by measuring urinary creatinine and albumin. Results: Our study demonstrate that anti-NBL1 monoclonal antibodies markedly reduced NBL1-induced podocyte death in vitro and rescued the expression of podocyte markers in human kidney organoids, upon NBL1 treatment. More importantly, when administered in vivo, anti-NBL1 prevented the increase of urinary albumin and creatinine, commonly observed in mice developing DKD. Also, NBL1 blockade reduced mesangial expansion and collagen deposition, as evidenced by PAS and Masson trichrome staining of kidney sections. Finally, anti-NBL1 ameliorated fibrosis and cell death by reducing expression of specific markers. Conclusion: Therapies aimed at preventing DKD onset and/or delaying progression to ESKD in patients with diabetes are still missing. Our findings demonstrate that NBL1 trigger DKD and/or accelerate its progression and that NBL1 blockade protect podocytes from death in vitro and diabetic mice in vivo from renal damage, thereby confirming the clinical relevance of targeting NBL1 signaling in DKD.