title: Role of impaired Nrf2 activation in the pathogenesis of oxidative stress and inflammation in chronic tubulo-interstitial nephropathy.
abstract: BACKGROUND
  Tubulo-interstitial nephropathy (TIN) is a common cause of chronic kidney disease (CKD). Consumption of an adenine-containing diet causes the accumulation of 2,8-dihydroxyadenine in the renal tubules triggering intense chronic TIN and progressive CKD in rats. CKD in this model is associated with, and largely driven by, oxidative stress and inflammation. Oxidative stress and inflammation in rats with spontaneous focal segmental glomerulosclerosis and rats with CKD induced by 5/6 nephrectomy are associated with an impaired activation of nuclear factor-erythroid-2-related factor 2 (Nrf2) which is the master regulator of genes encoding many antioxidant and detoxifying enzymes. The effect of TIN on the Nrf2 pathway and its key target genes is unknown and was investigated here.
  
  
  METHODS
  Sprague-Dawley rats were randomized to control and adenine-treated (rat chow-containing 0.7% adenine for 2 weeks) groups and followed up for 4 weeks.
  
  
  RESULTS
  The adenine-treated animals exhibited marked azotemia, impaired urinary concentrating capacity, intense tubular and glomerular damage, interstitial inflammation and fibrosis. This was associated with an increased expression of NAD(P)H oxidase, cyclooxygenase-2 and 12-lipoxygenase, and activation of NF-κB, the master regulator of pro-inflammatory cytokines and chemokines. Oxidative stress and inflammation in the kidneys of adenine-treated animals was accompanied by an impaired activation of Nrf2 and down-regulation of its target gene products including, catalase, heme oxygenase-1 and glutamate-cysteine ligase.
  
  
  CONCLUSIONS
  Chronic TIN is associated with impaired Nrf2 activity which contributes to the pathogenesis of oxidative stress and inflammation and amplifies their damaging effects on the kidney.
authors.affiliation: Division of Nephrology and Hypertension, University of California, Irvine, CA, USA.
authors.forename: Mohammad A
authors.initials: MA
authors.lastname: Aminzadeh
authors.forename: Susanne B
authors.initials: SB
authors.lastname: Nicholas
authors.forename: Keith C
authors.initials: KC
authors.lastname: Norris
authors.forename: Nosratola D
authors.initials: ND
authors.lastname: Vaziri
mesh_terms: D000225:Adenine / Q000633:toxicity; D000818:Animals; D001092:Arachidonate 12-Lipoxygenase / Q000378:metabolism; D015153:Blotting, Western; D002374:Catalase / Q000378:metabolism; D002908:Chronic Disease; D051546:Cyclooxygenase 2 / Q000378:metabolism; D005721:Glutamate-Cysteine Ligase / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000378:metabolism; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*; D008297:Male; D019255:NADPH Oxidases / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D009395:Nephritis, Interstitial / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology*; D018384:Oxidative Stress; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D051267:NF-E2-Related Factor 2; D016328:NF-kappa B; D002374:Catalase; D001092:Arachidonate 12-Lipoxygenase; D051547:Heme Oxygenase-1; D051546:Cyclooxygenase 2; D019255:NADPH Oxidases; D005721:Glutamate-Cysteine Ligase; D000225:Adenine
keywords: CKD progression; antioxidants; chronic kidney disease; reactive oxygen species