title: Acetaminophen attenuates glomerulosclerosis in obese Zucker rats via reactive oxygen species/p38MAPK signaling pathways.
abstract: Focal segmental glomerulosclerosis is a critical pathological lesion in metabolic syndrome-associated kidney disease that, if allowed to proceed unchecked, can lead to renal failure. However, the exact mechanisms underlying glomerulosclerosis remain unclear, and effective prevention strategies against glomerulosclerosis are currently limited. Herein, we demonstrate that chronic low-dose ingestion of acetaminophen (30 mg/kg/day for 6 months) attenuates proteinuria, glomerulosclerosis, podocyte injury, and inflammation in the obese Zucker rat model of metabolic syndrome. Moreover, acetaminophen treatment attenuated renal fibrosis and the expression of profibrotic factors (fibronectin, connective tissue growth factor, transforming growth factor β), reduced inflammatory cell infiltration into the glomeruli, and decreased the expression of monocyte chemoattractant protein, glutathione (GSH) reductase, and nuclear factor erythroid 2-related factor 2, but increased the level of GSH synthetase in obese animals. Further in vivo and in vitro studies using human renal mesangial cells exposed to high glucose or hydrogen peroxide suggested that the renoprotective effects of acetaminophen are characterized by diminished renal oxidative stress and p38MAPK hyperphosphorylation.
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
authors.initials: E
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: Huntington VA Medical Center, Huntington, WV 25704, USA.
authors.forename: William E
authors.initials: WE
authors.lastname: Triest
authors.affiliation: Huntington VA Medical Center, Huntington, WV 25704, USA.
authors.forename: John W
authors.initials: JW
authors.lastname: Leidy
authors.affiliation: Department of Internal Medicine, Joan C. Edwards School of Medicine, Huntington, WV 25755, USA.
authors.forename: Yanal
authors.initials: Y
authors.lastname: Masannat
authors.affiliation: Center for Diagnostic Nanosystems, Marshall University, Huntington, WV 25755, USA; School of Pharmacy, Marshall University, Huntington, WV 25755, USA; Department of Internal Medicine, Joan C. Edwards School of Medicine, Huntington, WV 25755, USA. Electronic address: wum@marshall.edu.
authors.forename: Miaozong
authors.initials: M
authors.lastname: Wu
mesh_terms: D000082:Acetaminophen / Q000494:pharmacology*; D000818:Animals; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D055513:Connective Tissue Growth Factor / Q000235:genetics / Q000378:metabolism; D005353:Fibronectins / Q000235:genetics / Q000378:metabolism; D005355:Fibrosis; D005786:Gene Expression Regulation; D005923:Glomerulosclerosis, Focal Segmental / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005980:Glutathione Reductase / Q000235:genetics / Q000378:metabolism; D005981:Glutathione Synthase / Q000235:genetics / Q000378:metabolism; D008233:Lymphotoxin-alpha / Q000235:genetics / Q000378:metabolism; D008297:Male; D050527:Mesangial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D024821:Metabolic Syndrome / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress; D061251:Primary Cell Culture; D051381:Rats; D011924:Rats, Zucker; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: C526316:CCN2 protein, rat; D018932:Chemokine CCL2; D005353:Fibronectins; D008233:Lymphotoxin-alpha; D051267:NF-E2-Related Factor 2; C495637:Nfe2l2 protein, rat; D017382:Reactive Oxygen Species; D055513:Connective Tissue Growth Factor; D000082:Acetaminophen; D005980:Glutathione Reductase; D048051:p38 Mitogen-Activated Protein Kinases; D005981:Glutathione Synthase
keywords: Acetaminophen; Free radicals; Glomerulosclerosis; Glutathione synthetase; Human renal mesangial cell; Obese Zucker rat; Oxidative stress; p38MAPK