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.

CONCLUSION:

Thus, pharmacological inhibition of NADPH oxidase can be protective for cisplatin-induced nephrotoxicity in mice.

• Authors: Yimin Wang, Xiao Luo, Hao Pan, Wei Huang, Xueping Wang, Huali Wen, Kezhen Shen, Baiye Jin
• Journal: Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association (Food Chem Toxicol) Vol. 83 Pg. 251-60 (Sep 2015) ISSN: 1873-6351 [Electronic] England
• PMID: 26032634 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015. Published by Elsevier Ltd.

Chemical References

• Acetophenones
• Antineoplastic Agents
• Biomarkers
• Enzyme Inhibitors
• Protective Agents
• acetovanillone
• NADPH Oxidases
• Cisplatin

Topics

• Acetophenones (administration & dosage, adverse effects, pharmacology, therapeutic use)
• Animals
• Antineoplastic Agents (adverse effects, chemistry, pharmacology)
• Apoptosis (drug effects)
• Biomarkers (blood, metabolism)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cisplatin (adverse effects, antagonists & inhibitors, pharmacology)
• Dose-Response Relationship, Drug
• Enzyme Inhibitors (administration & dosage, adverse effects, pharmacology, therapeutic use)
• Kidney (drug effects, metabolism, pathology, physiopathology)
• Male
• Mice, Inbred C57BL
• NADPH Oxidases (antagonists & inhibitors, metabolism)
• Oxidative Stress (drug effects)
• Picrorhiza (chemistry)
• Plant Roots (chemistry)
• Protective Agents (administration & dosage, adverse effects, pharmacology, therapeutic use)
• Renal Insufficiency (chemically induced, metabolism, pathology, physiopathology, prevention & control)