title: Metabolic syndrome-induced tubulointerstitial injury: role of oxidative stress and preventive effects of acetaminophen.
abstract: 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.
authors.affiliation: Center for Diagnostic Nanosystems, Marshall University, Huntington, WV 25755, USA; School of Pharmacy, Marshall University, Huntington, WV 25755, USA; Southeast University, Nanjing, Jiangsu, China.
authors.forename: Cuifen
authors.initials: C
authors.lastname: Wang
authors.affiliation: Center for Diagnostic Nanosystems, Marshall University, Huntington, WV 25755, USA; School of Pharmacy, Marshall University, Huntington, WV 25755, USA. Electronic address: blough@marshall.edu.
authors.forename: Eric R
authors.initials: ER
authors.lastname: Blough
authors.affiliation: Center for Diagnostic Nanosystems, Marshall University, Huntington, WV 25755, USA; School of Pharmacy, Marshall University, Huntington, WV 25755, USA.
authors.forename: Ravikumar
authors.initials: R
authors.lastname: Arvapalli
authors.affiliation: Southeast University, Nanjing, Jiangsu, China.
authors.forename: Xiaoniu
authors.initials: X
authors.lastname: Dai
authors.affiliation: Center for Diagnostic Nanosystems, Marshall University, Huntington, WV 25755, USA.
authors.forename: Satyanarayana
authors.initials: S
authors.lastname: Paturi
authors.affiliation: Center for Diagnostic Nanosystems, Marshall University, Huntington, WV 25755, USA; Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25755, USA.
authors.forename: Nandini
authors.initials: N
authors.lastname: Manne
authors.affiliation: Center for Diagnostic Nanosystems, Marshall University, Huntington, WV 25755, USA.
authors.forename: Hari
authors.initials: H
authors.lastname: Addagarla
authors.affiliation: Huntington Veterans Affairs Medical Center, Huntington, WV 25704, USA.
authors.forename: William E
authors.initials: WE
authors.lastname: Triest
authors.affiliation: Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25755, USA.
authors.forename: Omolola
authors.initials: O
authors.lastname: Olajide
authors.affiliation: Center for Diagnostic Nanosystems, Marshall University, Huntington, WV 25755, USA; School of Pharmacy, Marshall University, Huntington, WV 25755, USA; Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25755, USA. Electronic address: wum@marshall.edu.
authors.forename: Miaozong
authors.initials: M
authors.lastname: Wu
mesh_terms: D000082:Acetaminophen / Q000627:therapeutic use*; D000199:Actins / Q000096:biosynthesis; D018712:Analgesics, Non-Narcotic / Q000627:therapeutic use; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000096:biosynthesis; D055513:Connective Tissue Growth Factor / Q000096:biosynthesis; D058750:Epithelial-Mesenchymal Transition; D005355:Fibrosis / Q000188:drug therapy / Q000517:prevention & control; D015870:Gene Expression / Q000187:drug effects; D007249:Inflammation / Q000188:drug therapy; D007684:Kidney Tubules / Q000187:drug effects* / Q000293:injuries; D007797:Laminin / Q000096:biosynthesis; D008297:Male; D008562:Membrane Glycoproteins / Q000096:biosynthesis; D024821:Metabolic Syndrome / Q000473:pathology*; D000074662:NADPH Oxidase 2; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000096:biosynthesis; D009395:Nephritis, Interstitial / Q000188:drug therapy* / Q000517:prevention & control; D018384:Oxidative Stress / Q000187:drug effects*; D051381:Rats; D011924:Rats, Zucker; D016212:Transforming Growth Factor beta / Q000096:biosynthesis; D051028:bcl-2-Associated X Protein / Q000096:biosynthesis
chemical_list: D000082:Acetaminophen; D000199:Actins; D018712:Analgesics, Non-Narcotic; D053148:Caspase 3; D055513:Connective Tissue Growth Factor; D007797:Laminin; D008562:Membrane Glycoproteins; D000074662:NADPH Oxidase 2; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; D016212:Transforming Growth Factor beta; D051028:bcl-2-Associated X Protein; C498862:Acta2 protein, rat; C500593:Cybb protein, rat; C498911:Nox4 protein, rat
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