Nox2 and Cyclosporine-Induced Renal Hypoxia. Issue 6 (June 2016)

• Record Type: Journal Article
• Authors: Djamali, Arjang; Wilson, Nancy A.; Sadowski, Elizabeth A.; Zha, Wei; Niles, David; Hafez, Omeed; Dorn, Justin R.; Mehner, Thomas R.; Grimm, Paul C.; Hoffmann, F. Michael; Zhong, Weixiong; Fain, Sean B.; Reese, Shannon R.
• Is Part Of: Transplantation. Volume 100:Issue 6(2016)
• Publication Date: 2016-06
• Subjects: Transplantation of organs, tissues, etc -- Periodicals; Transplantation immunology -- Periodicals; 617.95
• DOI: 10.1097/TP.0000000000001137
• Languages: English
• ISSNs: 0041-1337

Abstract

Abstract : Background: We hypothesized that nicotinamide adenosine diphosphate oxidase 2 (Nox2) plays an important role in cyclosporine A (CsA)-induced chronic hypoxia. Methods: We tested this hypothesis in Fisher 344 rats, C57BL/6 J wild type and Nox2−/− mice, and in liver transplant recipients with chronic CsA nephrotoxicity. We used noninvasive molecular imaging (blood oxygen level-dependent magnetic resonance imaging and dynamic contrast-enhanced magnetic resonance imaging) and molecular diagnostic tools to assess intrarenal oxygenation and perfusion, and the molecular phenotype of CsA nephrotoxicity. Results: We observed that chemical and genetic inhibition of Nox2 in rats and mice resulted in the prevention of CsA-induced hypoxia independent of regional perfusion (blood oxygen level-dependent magnetic resonance imaging and dynamic contrast-enhanced magnetic resonance imaging, pimonidazole, HIF-1α). Nicotinamide adenosine diphosphate oxidase 2 knockout was also associated with decreased oxidative stress (Nox2, HIF-1α, hydrogen peroxide, hydroxynonenal), and fibrogenesis (α-smooth muscle actin, picrosirius red, trichrome, vimentin). The molecular signature of chronic CsA nephrotoxicity using transcriptomic analyses demonstrated significant changes in 40 genes involved in injury repair, metabolism, and oxidative stress in Nox2−/− mice. Immunohistochemical analyses of kidney biopsies from liver transplant recipients with chronic CsA nephrotoxicity showed significantly greater Nox2, α-smooth muscle actin and picrosirius levels compared with controls. Conclusions: These studies suggest that Nox2 is a modulator of CsA-induced hypoxia upstream of HIF-1α and define the molecular characteristics that could be used for the diagnosis and monitoring of chronic calcineurin inhibitor nephrotoxicity. Abstract : The authors suggest that Nox2 plays a critical role in cyclosporine A (CsA) - induced chronic hypoxia. Nox2 regulates oxidative stress, cell transport and injury repair through HIF signaling and metabolic pathways. Supplemental digital content is available in the text.