S M TAN1, V THALLAS-BONKE2, G HIGGINS1, R LINDBLOM1, M SNELSON1, C GRANATA1, J C JHA1, K SOURRIS1, M TAUC3, I RUBERA3, G ZHENG4, D HARRIS4, H SCHMIDT5, P KANTHARIDIS1, M COOPER1, K JANDELEIT-DAHM1, M COUGHLAN1
1Department of Diabetes, Monash University, 2Baker Heart and Diabetes Institute, 3University of Nice Sophia Antipolis, 4Centre for Transplantation and Renal Research, University of Sydney, 5Department of Pharmacology and Personalised Medicine, Maastricht University
Aim: To explore whether proximal tubule-derived Nox4 was essential for the development of diabetic kidney disease.
Background: The NADPH oxidase isoform, Nox4, mediates reactive oxygen species (ROS) production and renal fibrosis in diabetic kidney disease at the level of the podocyte, however its mitochondrial localization and role as a mitochondrial bioenergetic sensor has recently been reported. Whether Nox4 drives pathology in diabetic kidney disease within the proximal tubular compartment, which is densely packed with mitochondria, is not yet known.
Methods: We generated a proximal tubular specific Nox4 knockout mouse model by breeding Nox4flox/flox mice with mice expressing Cre recombinase under the control of the Sglt2 promoter. Subsets of PT-Nox4-/- mice and their wild type littermates were injected with streptozotocin (STZ) to induce diabetes. Mice were followed for 20 weeks and renal injury was assessed.
Results: Genetic ablation of proximal tubular Nox4 (PT-Nox4-/-) resulted in no change in renal function and histology. PT-Nox4-/- mice and wildtype littermates injected with STZ exhibited the hallmarks of diabetic kidney disease including hyperfiltration, albuminuria, renal fibrosis and glomerulosclerosis. Surprisingly, diabetes-induced renal injury was not improved in PT-Nox4-/- STZ mice compared to wildtype STZ mice. Although diabetes conferred ROS overproduction, proximal tubular deletion of Nox4 did not normalize oxidative stress status.
Conclusion: Taken together, these results demonstrate that genetic deletion of Nox4 from the proximal tubules does not influence diabetic kidney disease development, indicating that Nox4 localization within this highly energetic compartment is dispensable for chronic kidney disease pathogenesis.
Dr Tan is a research fellow at the Department of Diabetes, Monash University and the recipient of a Juvenile Diabetes Research Foundation Advanced Postdoctoral Fellowship. She is currently working on identifying new therapeutic targets for diabetic kidney disease with a specific focus on the role of the complement system.