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Am J Transl Res 2012;4(3):257-268
Original Article
Salutary effects of a novel oxidative stress modulator on adenine-
induced chronic progressive tubulointerstitial nephropathy
Susanne B Nicholas, Jun Yuan, Amin Aminzadeh, Keith C Norris, Albert Crum, Nosratola D Vaziri
Division of Nephrology and Division of Endocrinology, Diabetes and Hypertension, David Geffen School of
Medicine at University of California, Los Angeles, CA, USA; Department of Research, Charles R Drew University of
Medicine and Science, Los Angeles, CA, USA; Division of Nephrology, University of California, Irvine, CA, USA;
Proimmune®, Rhinebeck, New York, NY, USA
Received May 15, 2012; accepted June 7, 2012; Epub July 20 20, 2012; Published August 15, 2012
Abstract: Background: Oxidative stress and inflammation promote the development and progression of chronic
kidney disease. Oxidative stress is associated with depletion of tissue glutathione (GSH), the most abundant
endogenous intracellular antioxidant, but degradation of oral GSH by digestive enzymes limits its therapeutic use.
We hypothesized that GSH repletion with F1, a novel oral GSH precursor containing cystine as a cysteine carrier,
would restore tissue GSH and attenuate oxidative stress and inflammation, and thereby reduce the severity of
interstitial nephropathy in chronic renal failure (CRF). Methods: Male Sprague-Dawley rats (n=5-8) were assigned
to 3 groups: Control (regular rat chow), CRF (rat chow containing 0.7% adenine), and F1-treated CRF (rat chow
containing 0.7% adenine and F1, 0.5g/kg/day) for 2-weeks. Animals were switched to regular chow and
euthanized after 2 additional weeks. Results: Consumption of 0.7% adenine-containing diet caused azotemia;
severe kidney swelling; heavy tubular and glomerular damage; massive tubulointerstitial nephropathy; impaired
urinary concentrating capacity; severe anemia; increased markers of oxidative stress, plasma oxidized
glutathione disulfide (GSSG); reduced GSH/GSSG ratio and manganese superoxide dismutase; increased
expression of inflammatory mediators (cyclooxygenase-2, cytoplasmic NF-κB, p-IκBα, nuclear NF-κB p65), and 3-
nitrotyrosine, p<0.05. Co-treatment with F1 significantly attenuated tubulointerstitial inflammation and edema,
improved urinary concentrating capacity, azotemia and anemia, and normalized markers of tissue oxidative and
nitrosative stress, p<0.05. Conclusions: The novel oxidative stress modulator, F1, markedly attenuated oxidative
stress indicators, inflammation, renal injury and dysfunction in the rat model of CRF. Studies to determine the
effects of F1 in other models of acute and CRF are warranted. (AJTR1205001).
Keywords: Glutathione precursor, oxidative stress modulator, inflammation, glutathione disulfide, p-IκBα, NF-κB,
NF-κB p65, hematocrit
Address all correspondence to:
Dr. Susanne B Nicholas
Department of Medicine
Division of Nephrology and Endocrinology
900 Veteran Avenue, Suite 24-130
Los Angeles, CA 90095, USA.
Tel: 310-794-7550; Fax: 310-794-7654
E-mail: sunicholas@mednet.ucla.edu
Original Article
Salutary effects of a novel oxidative stress modulator on adenine-
induced chronic progressive tubulointerstitial nephropathy
Susanne B Nicholas, Jun Yuan, Amin Aminzadeh, Keith C Norris, Albert Crum, Nosratola D Vaziri
Division of Nephrology and Division of Endocrinology, Diabetes and Hypertension, David Geffen School of
Medicine at University of California, Los Angeles, CA, USA; Department of Research, Charles R Drew University of
Medicine and Science, Los Angeles, CA, USA; Division of Nephrology, University of California, Irvine, CA, USA;
Proimmune®, Rhinebeck, New York, NY, USA
Received May 15, 2012; accepted June 7, 2012; Epub July 20 20, 2012; Published August 15, 2012
Abstract: Background: Oxidative stress and inflammation promote the development and progression of chronic
kidney disease. Oxidative stress is associated with depletion of tissue glutathione (GSH), the most abundant
endogenous intracellular antioxidant, but degradation of oral GSH by digestive enzymes limits its therapeutic use.
We hypothesized that GSH repletion with F1, a novel oral GSH precursor containing cystine as a cysteine carrier,
would restore tissue GSH and attenuate oxidative stress and inflammation, and thereby reduce the severity of
interstitial nephropathy in chronic renal failure (CRF). Methods: Male Sprague-Dawley rats (n=5-8) were assigned
to 3 groups: Control (regular rat chow), CRF (rat chow containing 0.7% adenine), and F1-treated CRF (rat chow
containing 0.7% adenine and F1, 0.5g/kg/day) for 2-weeks. Animals were switched to regular chow and
euthanized after 2 additional weeks. Results: Consumption of 0.7% adenine-containing diet caused azotemia;
severe kidney swelling; heavy tubular and glomerular damage; massive tubulointerstitial nephropathy; impaired
urinary concentrating capacity; severe anemia; increased markers of oxidative stress, plasma oxidized
glutathione disulfide (GSSG); reduced GSH/GSSG ratio and manganese superoxide dismutase; increased
expression of inflammatory mediators (cyclooxygenase-2, cytoplasmic NF-κB, p-IκBα, nuclear NF-κB p65), and 3-
nitrotyrosine, p<0.05. Co-treatment with F1 significantly attenuated tubulointerstitial inflammation and edema,
improved urinary concentrating capacity, azotemia and anemia, and normalized markers of tissue oxidative and
nitrosative stress, p<0.05. Conclusions: The novel oxidative stress modulator, F1, markedly attenuated oxidative
stress indicators, inflammation, renal injury and dysfunction in the rat model of CRF. Studies to determine the
effects of F1 in other models of acute and CRF are warranted. (AJTR1205001).
Keywords: Glutathione precursor, oxidative stress modulator, inflammation, glutathione disulfide, p-IκBα, NF-κB,
NF-κB p65, hematocrit
Address all correspondence to:
Dr. Susanne B Nicholas
Department of Medicine
Division of Nephrology and Endocrinology
900 Veteran Avenue, Suite 24-130
Los Angeles, CA 90095, USA.
Tel: 310-794-7550; Fax: 310-794-7654
E-mail: sunicholas@mednet.ucla.edu
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