Abstract
NADPH oxidase 4 (NOX4) is highly expressed in kidney proximal tubular cells. NOX4 constitutively produces hydrogen peroxide, which may regulate important pro-survival pathways. Renal ischemia reperfusion injury (IRI) is a classical model mimicking human ischemic acute tubular necrosis. We hypothesized that NOX4 plays a protective role in kidney IRI. In wild type (WT) animals subjected to IRI, NOX4 protein expression increased after 24 hours. NOX4 KO (knock-out) and WT littermates mice were subjected to IRI. NOX4 KO mice displayed decreased renal function and more severe tubular apoptosis, decreased Bcl-2 expression and higher histologic damage scores compared to WT. Activation of NRF2 was decreased in NOX4 KO mice in response to IRI. This was related to decreased KEAP1 oxidation leading to decreased NRF2 stabilization. This resulted in decreased glutathione levels. In vitro silencing of NOX4 in cells showed an enhanced propensity to apoptosis, with reduced expression of NRF2, glutathione content and Bcl-2 expression, similar to cells derived from NOX4 KO mice. Overexpression of a constitutively active form of NRF2 (caNRF2) in NOX4 depleted cells rescued most of this phenotype in cultured cells, implying that NRF2 regulation by ROS issued from NOX4 may play an important role in its anti-apoptotic property.
Highlights
This page was generated automatically upon download from the ETH Zurich Research Collection
We demonstrate that NADPH oxidase 4 (NOX4) deletion enhances tubular apoptosis in response to ischemia reperfusion injury (IRI) in the kidney
We further show that part of this phenotype is in part related to regulation of Bcl-2 via changes in Nuclear factor (erythroid-derived 2)-like 2 (NRF2) regulation and oxidation of KEAP1
Summary
This page was generated automatically upon download from the ETH Zurich Research Collection. Activation of NRF2 was decreased in NOX4 KO mice in response to IRI This was related to decreased KEAP1 oxidation leading to decreased NRF2 stabilization. NADPH oxidases are enzymes producing free radicals as their main product[1] Their respective role is determined by their regulation and localization. Previous research demonstrated that NOX4 expression was increased in various types of kidney disease, such as diabetic and hypertensive nephropathies, where it may play a deleterious role[5,6,7]. Glomerular lesions of diabetic nephropathy appear either unchanged or rescued by NOX4 deletion, depending on the model used[12,14,15] These seemingly contradictory results indicate that NOX4 possesses a cell-specific role, with a physiological role in compartments where it is highly expressed such as in tubular cells. Results are expressed as the mean of individual densitometric values over the mean densitometric value obtained in sham operated animals ±SE, ns p > 0.05 and *p < 0.05
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: 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.
