Journal article
Nox2 and Cyclosporine-Induced Renal Hypoxia
Transplantation, Vol.100(6), pp.1198-1210
06/01/2016
DOI: 10.1097/TP.0000000000001137
PMCID: PMC4874919
PMID: 26950727
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-1 alpha). Nicotinamide adenosine diphosphate oxidase 2 knockout was also associated with decreased oxidative stress (Nox2, HIF-1 alpha, hydrogen peroxide, hydroxynonenal), and fibrogenesis (a-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, alpha-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-1a and define the molecular characteristics that could be used for the diagnosis and monitoring of chronic calcineurin inhibitor nephrotoxicity.
Details
- Title: Subtitle
- Nox2 and Cyclosporine-Induced Renal Hypoxia
- Creators
- Arjang Djamali - University of Wisconsin–MadisonNancy A. Wilson - Univ Wisconsin, Dept Med, Div Nephrol, Madison, WI USAElizabeth A. Sadowski - Univ Wisconsin, Dept Radiol, Madison, WI 53706 USAWei Zha - Univ Wisconsin, Dept Med Phys, 1530 Med Sci Ctr, Madison, WI 53706 USADavid Niles - Univ Wisconsin, Dept Med Phys, 1530 Med Sci Ctr, Madison, WI 53706 USAOmeed Hafez - Univ Wisconsin, Dept Med, Div Nephrol, Madison, WI USAJustin R. Dorn - Univ Wisconsin, Dept Med, Div Nephrol, Madison, WI USAThomas R. Mehner - Univ Wisconsin, Dept Med, Div Nephrol, Madison, WI USAPaul C. Grimm - Stanford UniversityF. Michael Hoffmann - Univ Wisconsin, McArdle Inst, Ctr Canc, Madison, WI USAWeixiong Zhong - Univ Wisconsin, Dept Pathol & Lab Med, Madison, WI USASean B. Fain - Univ Wisconsin, Dept Med Phys, 1530 Med Sci Ctr, Madison, WI 53706 USAShannon R. Reese - Univ Wisconsin, Dept Med, Div Nephrol, Madison, WI USA
- Resource Type
- Journal article
- Publication Details
- Transplantation, Vol.100(6), pp.1198-1210
- DOI
- 10.1097/TP.0000000000001137
- PMID
- 26950727
- PMCID
- PMC4874919
- NLM abbreviation
- Transplantation
- ISSN
- 0041-1337
- eISSN
- 1534-6080
- Publisher
- Lippincott Williams & Wilkins
- Number of pages
- 13
- Grant note
- 5R01DK092454-04 / NIDDK; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK) R01DK092454 / NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK)
- Language
- English
- Date published
- 06/01/2016
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Radiology; Electrical and Computer Engineering; Health, Sport, and Human Physiology
- Record Identifier
- 9984275057602771
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