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Background: Renal oxidative stress plays an important role in mediating kidney injury in diabetes. There is increasing evidences that recently discovered pro-oxidant enzyme, Nox5 plays a significant role in human diabetic kidney disease (DKD). We examined the role of Nox5 in human DKD, in human renal cell populations as well as in a high fat fed and alloxan rabbit model of DKD. In addition, we also examined the contribution of Nox5 in the in DKD in the absence of Nox4 expression using renal cell specific Nox5Tg mice. Results: Expression of Nox5 was increased in both glomerular and tubular compartments of kidney biopsies obtained from diabetic individuals. Nox5 is the Nox isoform which shows the highest upregulation in response to high glucose. Silencing of Nox5 reduces ROS formation and expression of proinflammatory and profibrotic cytokines and growth factors as well as putative elements that are implicated in DKD. Our data also suggest that Nox5 is upstream of Nox4 and that Nox5 inhibition downregulates Nox4, but not vice versa. High fat feeding and alloxan induced diabetes rabbits showed upregulation of Nox5 and increased ROS in association with increased mesangial area, ECM protein accumulation and upregulation of a range of pro-inflammatory (MCP-1) and pro-fibrotic genes (CTGF) as analysed by RNAseq and confirmed by RT-PCR. In addition, over expression of Nox5 in mesangial cells of Nox4 KO diabetic mice demonstrated 30% increase in albuminuria, mesangial expansion, increased renal injury and inflammation via enhanced ROS production. Conclusions: These studies will for the first time explore in a comprehensive manner the role of Nox5 in recently generated Nox5KO rabbit models in the context of type 1 and type 2 diabetes as well as delineate the relative role of Nox4 versus Nox5 in diabetic complications. These studies will provide evidence if Nox5 blockade alone or combined with Nox4/Nox5 blockade is the optimal approach to treat and prevent diabetic complications, in particular nephropathy. Disclosure: J.C. Jha: None. M.E. Cooper: Advisory Panel; Self; AstraZeneca, Lilly Diabetes. Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Servier. Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Novo Nordisk A/S. Speaker's Bureau; Self; Bayer AG, Merck Sharp & Dohme Corp., Novartis AG. C. Kennedy: Research Support; Self; Prometic Life Sciences Inc. K. Jandeleit-Dahm: Advisory Panel; Self; Australian Diabetes Society, Genkyotex. Consultant; Self; Metavention. [ABSTRACT FROM AUTHOR]