Abstract
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, the mitochondrial localization of Nox4 and its 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 Nox4ptKO mice and their Nox4flox/flox 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 (Nox4ptKO) resulted in no change in renal function and histology. Nox4ptKO mice and Nox4flox/flox 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 Nox4ptKOSTZ mice compared to Nox4flox/flox STZ mice. Although diabetes conferred ROS overproduction and increased mitochondrial oxygen consumption rate, proximal tubular deletion of Nox4 did not normalize oxidative stress or mitochondrial bioenergetics.
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 in the setting of diabetes.
Urinary Periostin as an Early Predictor of Renal Injury in Diabetic Kidney Disease: A Tertiary Centre Experience
