Contribution of impaired Nrf2-Keap1 pathway to oxidative stress and inflammation in chronic renal failure.
Oxidative stress and inflammation are constant features and major mediators of progression of chronic kidney disease (CKD). Nuclear factor erythroid-2-related factor-2 (Nrf2) confers protection against tissue injury by orchestrating antioxidant and detoxification responses to oxidative and electrophilic stress. While sources of oxidative stress and inflammation in the remnant kidney have been extensively characterized, the effect of CKD on Nrf2 activation and expression of its downstream gene products is unknown and was investigated. Subgroups of male Sprague-Dawley rats were subjected to 5/6 nephrectomy or sham operation and observed for 6 or 12 wk. Kidneys were then harvested, and Nrf2 activity and its downstream target gene products (antioxidant and phase II enzymes) were assessed. In addition, key factors involved in promoting inflammation and oxidative stress were studied. In confirmation of earlier studies, rats with chronic renal failure exhibited increased lipid peroxidation, glutathione depletion, NF-kappaB activation, mononuclear cell infiltration, and upregulation of monocyte chemoattractant protein-1, NAD(P)H oxidase, cyclooxygenase-2, and 12-lipoxygenase in the remnant kidney pointing to oxidative stress and inflammation. Despite severe oxidative stress and inflammation, remnant kidney tissue Nrf2 activity (nuclear translocation) was mildly reduced at 6 wk and markedly reduced at 12 wk, whereas the Nrf2 repressor Keap1 was upregulated and the products of Nrf2 target genes [catalase, superoxide dismutase, glutathione peroxidase, heme oxygenase-1, NAD(P)H quinone oxidoreductase, and glutamate-cysteine ligase] were reduced or unchanged at 6 wk and significantly diminished at 12 wk. Thus oxidative stress and inflammation in the remnant kidney are compounded by conspicuous impairment of Nrf2 activation and consequent downregulation of the antioxidant enzymes.
Kim
Hyun Ju
HJ
Division of Nephrology and Hypertension, University of California, Irvine, California, USA.
Vaziri
Nosratola D
ND
D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D004798:Enzymes / Q000378:metabolism; D005978:Glutathione / Q000172:deficiency; D007249:Inflammation / Q000276:immunology / Q000378:metabolism*; D018836:Inflammation Mediators / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D000072019:Kelch-Like ECH-Associated Protein 1; D007668:Kidney / Q000201:enzymology / Q000276:immunology / Q000378:metabolism* / Q000601:surgery; D007676:Kidney Failure, Chronic / Q000276:immunology / Q000378:metabolism*; D015227:Lipid Peroxidation; D008297:Male; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D009392:Nephrectomy; D018384:Oxidative Stress; D011506:Proteins / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors
D000975:Antioxidants; D004798:Enzymes; D018836:Inflammation Mediators; D047908:Intracellular Signaling Peptides and Proteins; C486610:KEAP1 protein, rat; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; C495637:Nfe2l2 protein, rat; D011506:Proteins; D017382:Reactive Oxygen Species; D005978:Glutathione