title: Pharmacological inhibition of NADPH oxidase protects against cisplatin induced nephrotoxicity in mice by two step mechanism.
abstract: BACKGROUND
  Cisplatin induced nephrotoxicity is primarily caused by ROS (Reactive Oxygen Species) induced proximal tubular cell death. NADPH oxidase is major source of ROS production by cisplatin. Here, we reported that pharmacological inhibition of NADPH oxidase by acetovanillone (obtained from medicinal herb Picrorhiza kurroa) led to reduced cisplatin nephrotoxicity in mice.
  
  
  METHODS
  In this study we used various molecular biology and biochemistry methods a clinically relevant model of nephropathy, induced by an important chemotherapeutic drug cisplatin.
  
  
  RESULTS
  Cisplatin-induced nephrotoxicity was evident by histological damage from loss of the tubular structure. The damage was also marked by the increase in blood urea nitrogen, creatinine, protein nitration as well as cell death markers such as caspase 3/7 activity and DNA fragmentation. Tubular cell death by cisplatin led to pro-inflammatory response by production of TNFα and IL1β followed by leukocyte/neutrophil infiltration which resulted in new wave of ROS involving more NADPH oxidases. Cisplatin-induced markers of kidney damage such as oxidative stress, cell death, inflammatory cytokine production and nephrotoxicity were attenuated by acetovanillone. In addition to that, acetovanillone enhanced cancer cell killing efficacy of cisplatin.
  
  
  CONCLUSIONS
  Thus, pharmacological inhibition of NADPH oxidase can be protective for cisplatin-induced nephrotoxicity in mice.
authors.affiliation: Department of Urology, The First Affiliated Hospital, College of Medicine, Zhejiang University, #79 Qinchun Road, Hangzhou, Zhejiang 310003, China.
authors.forename: Yimin
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Urology, The First People's Hospital of Tongxiang City, Tongxiang, Zhejiang Province 314500, China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Luo
authors.affiliation: Department of Urology, The First Affiliated Hospital, College of Medicine, Zhejiang University, #79 Qinchun Road, Hangzhou, Zhejiang 310003, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Pan
authors.affiliation: Department of Urology, The People's Hospital of Yueqing City, Yueqing, Zhejiang Province 325600, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Huang
authors.affiliation: Department of Urology, The First Affiliated Hospital, College of Medicine, Zhejiang University, #79 Qinchun Road, Hangzhou, Zhejiang 310003, China.
authors.forename: Xueping
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Urology, The First Affiliated Hospital, College of Medicine, Zhejiang University, #79 Qinchun Road, Hangzhou, Zhejiang 310003, China.
authors.forename: Huali
authors.initials: H
authors.lastname: Wen
authors.affiliation: Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, Hangzhou, Zhejiang Province 310003, China.
authors.forename: Kezhen
authors.initials: K
authors.lastname: Shen
authors.affiliation: Department of Urology, The First Affiliated Hospital, College of Medicine, Zhejiang University, #79 Qinchun Road, Hangzhou, Zhejiang 310003, China. Electronic address: jinbaiye1964@aliyun.com.
authors.forename: Baiye
authors.initials: B
authors.lastname: Jin
mesh_terms: D000098:Acetophenones / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D015415:Biomarkers / Q000097:blood / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000009:adverse effects* / Q000037:antagonists & inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D008297:Male; D008810:Mice, Inbred C57BL; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D032261:Picrorhiza / Q000737:chemistry; D018517:Plant Roots / Q000737:chemistry; D020011:Protective Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D051437:Renal Insufficiency / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*
chemical_list: D000098:Acetophenones; D000970:Antineoplastic Agents; D015415:Biomarkers; D004791:Enzyme Inhibitors; D020011:Protective Agents; C056165:acetovanillone; D019255:NADPH Oxidases; D002945:Cisplatin
keywords: Kidney failure; NOX; Oncology; Oxidative stress; T24 cell line