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Objective: Diabetic nephropathy (DN), also known as diabetic kidney disea se (DKD), is a major chronic complication of diabetes and is the most frequent cause of kidney failure globa lly. A better understanding of the pathophysiology of DN would lead to the development of novel therapeutic options. Acrolein, an α,β-unsaturated aldehyde, is a common dietary and environmental pollutant. Design: The role of acrolein and the potential protective action of ac rolein scavengers in DN were investigated using high-fat diet/streptozotocin-induced DN mice and in vitro DN cellular models. Methods: Acrolein-protein conjugates (Acr-PCs) in kidney tissues were e xamined using immunohistochemistry. Renin-angiotensin system (RAS) and downstream signaling pathways were analyzed using quantitative RT-PCR and Western blot analyses. Acr-PCs in DN patients were analyzed using an es tablished Acr-PC ELISA system. Results: We found an increase in Acr-PCs in kidney cells using in vivo and in vitro DN models. Hyperglycemia activated the RAS and downstream MAPK pathways, increasing inflammatory cy tokines and cellular apoptosis in two human kidney cell lines (HK2 and HEK293). A similar effect was induced by acrolein. Furthermore, acrolein scavengers such as N-acetylcysteine, hydralazine, and carnosine could ameliorate diabetes-induced kidney injury. Clinically, we also found increased Acr-PCs in serum samples or kidney tissues of DKD pat ients compared to normal volunteers, and the Acr-PCs were negatively correlated with kidney function. Conclusions: These results together suggest that acrolein plays a role in the pathogenesis of DN and could be a diagnostic marker and effective therapeutic target to ameliorate the development of DN. [ABSTRACT FROM AUTHOR]