Abstract
Current treatments for diabetic nephropathy (DN) only result in slowing its progression, thus highlighting a need to identify novel targets. Increased production of reactive oxygen species (ROS) is considered a key downstream pathway of end‐organ injury with increasing data implicating both mitochondrial and cytosolic sources of ROS. The enzyme, NADPH oxidase, generates ROS in the kidney and has been implicated in the activation of protein kinase C (PKC), in the pathogenesis of DN, but the link between PKC and Nox‐derived ROS has not been evaluated in detail in vivo. In this study, global deletion of a NADPH‐oxidase isoform, Nox4, was examined in mice with streptozotocin‐induced diabetes (C57Bl6/J) in order to evaluate the effects of Nox4 deletion, not only on renal structure and function but also on the PKC pathway and downstream events. Nox4 deletion attenuated diabetes‐associated increases in albuminuria, glomerulosclerosis, and extracellular matrix accumulation. Lack of Nox4 resulted in a decrease in diabetes‐induced renal cortical ROS derived from the mitochondria and the cytosol, urinary isoprostanes, and PKC activity. Immunostaining of renal cortex revealed that major isoforms of PKC, PKC‐α and PKC‐β1, were increased with diabetes and normalized by Nox4 deletion. Downregulation of the PKC pathway was observed in tandem with reduced expression of vascular endothelial growth factor (VEGF), transforming growth factor (TGF)‐β1 and restoration of the podocyte slit pore protein nephrin. This study suggests that deletion of Nox4 may alleviate renal injury via PKC‐dependent mechanisms, further strengthening the view that Nox4 is a suitable target for renoprotection in diabetes.
Highlights
The prevalence of diabetic nephropathy (DN) rises each year (Shaw et al 2010), resulting in an increased number of individuals with endstage renal disease worldwide
Similar results were observed with protein kinase C (PKC)-b1, in which an increase in protein expression was found in the wildtype diabetic (WT-D) group with a significant reduction in the KO-D animals (Fig. 9A and B). These studies have focused on the role of deletion of Nox4 on the regulation of the PKC pathway in diabetic kidney disease (Fig. 10)
We have shown for the first time the renoprotective effects of global deletion of Nox4 in a model of streptozotocin-induced diabetes
Summary
The prevalence of DN rises each year (Shaw et al 2010), resulting in an increased number of individuals with endstage renal disease worldwide. A number of mechanisms have been implicated in the tissue-damaging effects of hyperglycemia, such as the polyol pathway (Yabe-Nishimura 1998), increased production of advanced glycation end-products (Brownlee et al 1988),. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.