Oxidative stress and dysregulation of superoxide dismutase and NADPH oxidase in renal insufficiency.
BACKGROUND
Chronic renal failure (CRF) is associated with oxidative stress, the mechanism of which remains uncertain. Superoxide is the primary oxygen free radical produced in the body, NAD(P)H oxidase is the major source of superoxide production and superoxide dismutase (SOD) is responsible for removal of superoxide. We hypothesized that CRF-induced oxidative stress may be due to increased production and/or decreased dismutation of superoxide.


METHODS
Immunodetectable superoxide dismutase isoforms (Cu Zn SOD and Mn SOD), as well as, NAD(P)H oxidase (gp91 phox subunit) proteins and xanthine oxidase (XO) activity were determined in the kidney and liver of CRF (5/6 nephrectomized) and sham-operated control rats. Subgroups of animals were treated with SOD-mimetic drug, tempol and blood pressure and urinary nitric oxide metabolites (NOx) were monitored.


RESULTS
The CRF group showed marked down-regulations of CuZn SOD and Mn SOD and significant up-regulation of gp91 phox in the liver and kidney, which are among the metabolically most active tissues. In contrast, XO activity was depressed in both tissues. Arterial pressure and nitrotyrosine abundance were elevated while urinary NOx excretion was depressed, pointing to increased NO inactivation by superoxide and decreased NO availability in CRF animals. Administration of SOD-mimetic agent, tempol, for one week, ameliorated hypertension, reduced nitrotyrosine abundance and increased urinary NOx excretion in the CRF animals.


CONCLUSIONS
CRF is associated with depressed SOD and elevated NAD(P)H oxidase expression, which can contribute to oxidative stress by increasing superoxide. This is evidenced by favorable response to administration of SOD-mimetic drug, tempol, and increased nitrotyrosine that is the footprint of NO interaction with superoxide.
Vaziri
Nosratola D
ND
Department of Medicine, Physiology and Biophysics, College of Medicine, University of California, Irvine, USA. ndvaziri@uci.edu
Dicus
Michael
M
Ho
Nathan D
ND
Boroujerdi-Rad
Laleh
L
Sindhu
Ram K
RK
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D003497:Cyclic N-Oxides / Q000494:pharmacology; D015536:Down-Regulation; D006977:Hypertension, Renal / Q000378:metabolism; D007668:Kidney / Q000201:enzymology; D007676:Kidney Failure, Chronic / Q000378:metabolism*; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism*; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013113:Spin Labels; D013482:Superoxide Dismutase / Q000378:metabolism*; D015854:Up-Regulation; D014969:Xanthine Oxidase / Q000378:metabolism
D000975:Antioxidants; D003497:Cyclic N-Oxides; D008562:Membrane Glycoproteins; D013113:Spin Labels; D013482:Superoxide Dismutase; D014969:Xanthine Oxidase; C056558:CYBB protein, human; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; C001803:tempol