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Nox2 and Cyclosporine-Induced Renal Hypoxia
Arjang Djamali1, Nancy A Wilson, Elizabeth A Sadowski
11 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.
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.
Insights
Nicotinamide adenosine diphosphate oxidase 2 (Nox2) prevents cyclosporine A-induced kidney hypoxia and damage. Inhibiting Nox2 reduces oxidative stress and fibrosis, offering diagnostic and monitoring insights for calcineurin inhibitor nephrotoxicity.
Area of Science:
- Nephrology
- Molecular Biology
- Medical Imaging
Background:
- Cyclosporine A (CsA) can induce chronic kidney hypoxia.
- The role of nicotinamide adenosine diphosphate oxidase 2 (Nox2) in this process is not fully understood.
Purpose of the Study:
- To investigate the role of Nox2 in CsA-induced chronic kidney hypoxia and nephrotoxicity.
- To identify molecular markers for diagnosing and monitoring CsA nephrotoxicity.
Main Methods:
- Tested hypothesis in rats, Nox2 knockout mice, and liver transplant recipients.
- Utilized noninvasive molecular imaging (MRI) and molecular diagnostic tools.
- Assessed intrarenal oxygenation, perfusion, and molecular phenotype.
Main Results:
- Nox2 inhibition prevented CsA-induced hypoxia and reduced oxidative stress and fibrosis.
- Transcriptomic analysis revealed significant gene expression changes in Nox2 knockout mice.
- Kidney biopsies showed increased Nox2, α-smooth muscle actin, and picrosirius levels in patients with CsA nephrotoxicity.
Conclusions:
- Nox2 modulates CsA-induced hypoxia upstream of HIF-1α.
- Identified molecular signatures for diagnosing and monitoring chronic calcineurin inhibitor nephrotoxicity.
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