title: Nox2 and Cyclosporine-Induced Renal Hypoxia.
abstract: We hypothesized that nicotinamide adenosine diphosphate oxidase 2 (Nox2) plays an important role in cyclosporine A (CsA)-induced chronic hypoxia.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: 1 Division of Nephrology, Department of Medicine, University of Wisconsin, Madison, WI. 2 Department of Radiology, University of Wisconsin, Madison, WI. 3 Department of Medical Physics, University of Wisconsin, Madison, WI. 4 Division of Pediatric Nephrology, Stanford University, San Francisco, CA. 5 McArdle Institute, University of Wisconsin Cancer Center, Madison, WI. 6 Department of Pathology and Laboratory Medicine, University of Wisconsin, Madison, WI.
authors.forename: Arjang
authors.initials: A
authors.lastname: Djamali
authors.forename: Nancy A
authors.initials: NA
authors.lastname: Wilson
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Sadowski
authors.forename: Wei
authors.initials: W
authors.lastname: Zha
authors.forename: David
authors.initials: D
authors.lastname: Niles
authors.forename: Omeed
authors.initials: O
authors.lastname: Hafez
authors.forename: Justin R
authors.initials: JR
authors.lastname: Dorn
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Mehner
authors.forename: Paul C
authors.initials: PC
authors.lastname: Grimm
authors.forename: F Michael
authors.initials: FM
authors.lastname: Hoffmann
authors.forename: Weixiong
authors.initials: W
authors.lastname: Zhong
authors.forename: Sean B
authors.initials: SB
authors.lastname: Fain
authors.forename: Shannon R
authors.initials: SR
authors.lastname: Reese
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D001391:Azo Compounds / Q000378:metabolism; D001706:Biopsy; D065095:Calcineurin Inhibitors / Q000737:chemistry; D003287:Contrast Media / Q000737:chemistry; D016572:Cyclosporine / Q000009:adverse effects*; D006861:Hydrogen Peroxide / Q000378:metabolism; D000860:Hypoxia / Q000139:chemically induced*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007668:Kidney / Q000187:drug effects* / Q000473:pathology*; D008099:Liver / Q000473:pathology; D016031:Liver Transplantation; D008279:Magnetic Resonance Imaging; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000235:genetics* / Q000378:metabolism; D010477:Perfusion; D010641:Phenotype; D051381:Rats; D011916:Rats, Inbred F344; D014746:Vimentin / Q000378:metabolism
chemical_list: D000199:Actins; D001391:Azo Compounds; D065095:Calcineurin Inhibitors; D003287:Contrast Media; C497443:Hif1a protein, mouse; C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008562:Membrane Glycoproteins; D014746:Vimentin; C009798:C.I. direct red 80; D016572:Cyclosporine; D006861:Hydrogen Peroxide; C488842:Cybb protein, mouse; C500593:Cybb protein, rat; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases