The prevalence of metabolic syndrome persistently increases and affects over 30% of U.S. adults. To study how metabolic syndrome may induce tubulointerstitial injury and whether acetaminophen has renal-protective properties, 4-week-old obese Zucker rats were randomly assigned into three groups, control (OC), vehicle dimethyl sulfoxide (OV), and acetaminophen treatment (30 mg/kg/day for 26 weeks), and lean Zucker rats served as healthy controls. Significant tubulointerstitial injuries were observed in both OC and OV animals, evidenced by increased tubular cell death, tubular atrophy/dilation, inflammatory cell infiltration, and fibrosis. These tubulointerstitial alterations were significantly reduced by treatment with a chronic but low dose of acetaminophen, which acted to diminish NADPH oxidase isoforms Nox2 and Nox4 and decrease tubulointerstitial oxidative stress (reduced tissue superoxide and macromolecular oxidation). Decreased oxidative stress by acetaminophen was paralleled by the reduction of tubular proapoptotic signaling (diminished Bax/Bcl-2 ratio and caspase 3 activation) and the alleviation of tubular epithelial-to-mesenchymal transition (decreased transforming growth factor β, connective tissue growth factor, α-smooth muscle actin, and laminin). These data suggest that increased oxidative stress plays a critical role in mediating metabolic syndrome-induced tubulointerstitial injury and provide the first evidence suggesting that acetaminophen may be of therapeutic benefit for the prevention of tubulointerstitial injury.
Keywords: 4-HNE; 4-hydroxynonenal; 8-OHdG; 8-hydroxydeoxyguanosine; APAP; Acetaminophen; CKD; CTGF; Cell death; DHE; DMSO; ECM; ESRD; Epithelial-to-mesenchymal transition; GAPDH; Metabolic syndrome; NAG; Oxidative stress; PSR; Picro-sirius red; ROS; TGF-β; TUNEL; Tubulointerstitial injury; acetaminophen; chronic kidney disease; connective tissue growth factor; dihydroethidium; dimethyl sulfoxide; end-stage renal disease; extracellular matrix; glyceraldehyde-3-phosphate dehydrogenase; reactive oxygen species; terminal deoxynucleotidyl transferase dUTP nick-end labeling; transforming growth factor β; α-SMA; α-smooth muscle actin; β-N-acetylglucosaminidase.
© 2013 The Authors. Published by Elsevier Inc. All rights reserved.