478-P: Nox5 Aggravates Renal Injury Independent of Nox4 Expression in Diabetes

Abstract

Background: Oxidative stress plays an important role in the pathogenesis of diabetic kidney disease (DKD). Evidences suggest roles for pro-oxidant enzymes Nox4 and Nox5 in animal models of DKD. Nox5 is present in mans but not in mice/rats. It appears that Nox5 could be a main culprit in human DKD. Therefore, we aimed to examine the roles of Nox5 vs. Nox4 and their relative contribution to renal pathology in DKD. Methods: We examined the expression and interaction of Nox5 and Nox4 and ROS formation in human kidney biopsies. In vitro, certain human renal cells being knockdown for Nox4 and Nox5 were exposed to high glucose. In vivo, we examined the effect of Nox5 expression in the absence of Nox4 in STZ- diabetic mice. We developed rabbit models of DKD and Nox5KO rabbits. Results: Increased Nox5 expression and enhanced ROS level was seen in human diabetic kidney biopsies compared to nondiabetic kidney. Nox5 shows the highest upregulation in human renal cells exposed to high glucose in comparison to other Nox isoforms. Nox5 silencing attenuated high glucose induced increased expression of markers of fibrosis, inflammation and putative elements via reduction in ROS formation. Nox5 appears to be upstream of Nox4 and that Nox5 inhibition downregulates Nox4, but not vice versa. In vivo, cell specific expression of Nox5 in both Nox4 KO and GKT137831 (a renal Nox4 inhibitor) treated diabetic mice demonstrated a 30-40% increase in albuminuria, mesangial expansion, renal fibrosis and inflammation as well as enhanced ROS production in comparison to diabetic mice not expressing Nox5. In addition, both high fat feeding and alloxan induced diabetic rabbits showed increased renal Nox5 expression in association with increased renal injury along with upregulation of CTGF, fibronectin and MCP-1 as well as enhanced renal ROS production. Conclusions: These findings provide evidence that Nox5 plays a superior pathogenic role in DKD in comparison to Nox4. Therefore, targeting Nox5 may represent a better approach to treat and prevent DKD in human. Disclosure J.C. Jha: None. S. Urner: None. A. Dai: None. M.E. Cooper: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Mundipharma International. Research Support; Self; Boehringer Ingelheim International GmbH, Novo Nordisk A/S. Speaker’s Bureau; Self; AstraZeneca, Merck Sharp & Dohme Corp., Novartis AG, Sanofi-Aventis, Servier. M. Roden: Advisory Panel; Self; Servier. Board Member; Self; Poxel SA. Consultant; Self; Eli Lilly and Company, Gilead Sciences, Inc., ProSciento, TARGET PharmaSolutions. Research Support; Self; Boehringer Ingelheim International GmbH, Novartis Pharma K.K., Sanofi US. Speaker’s Bureau; Self; Novo Nordisk A/S. C. Kennedy: None. K. Jandeleit-Dahm: None.