Yimin Wang1, Xiao Luo2, Hao Pan1, Wei Huang3, Xueping Wang1, Huali Wen1, Kezhen Shen4, Baiye Jin5. 1. Department of Urology, The First Affiliated Hospital, College of Medicine, Zhejiang University, #79 Qinchun Road, Hangzhou, Zhejiang 310003, China. 2. Department of Urology, The First People's Hospital of Tongxiang City, Tongxiang, Zhejiang Province 314500, China. 3. Department of Urology, The People's Hospital of Yueqing City, Yueqing, Zhejiang Province 325600, China. 4. Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, Hangzhou, Zhejiang Province 310003, China. 5. Department of Urology, The First Affiliated Hospital, College of Medicine, Zhejiang University, #79 Qinchun Road, Hangzhou, Zhejiang 310003, China. Electronic address: jinbaiye1964@aliyun.com.
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.
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 cisplatinnephrotoxicity 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 ureanitrogen, 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: Manoj Kumar; Parul Singh; Selvasankar Murugesan; Marie Vetizou; John McCulloch; Jonathan H Badger; Giorgio Trinchieri; Souhaila Al Khodor Journal: Methods Mol Biol Date: 2020