Shi-Kun Yang1, Ya-Chun Han2, Jin-Rong He3, Ming Yang4, Wei Zhang5, Ming Zhan6, Ai-Mei Li7, Liu Li8, Yu-Ting Liu9, Xue-Qin Wu10, Qin Zhang11, Jian-Wen Wang12, Hao Zhang13. 1. Department of Nephrology, The Third Xiangya Hospital, Central South University, Changsha, Hunan Province, China. Electronic address: yangshikun@csu.edu.cn. 2. Institute of Kidney Disease, Central South University, Changsha, Hunan Province, China. Electronic address: hanyachun@csu.edu.cn. 3. Department of Nephrology, The Third Xiangya Hospital, Central South University, Changsha, Hunan Province, China. Electronic address: 2990194461@qq.com. 4. Institute of Kidney Disease, Central South University, Changsha, Hunan Province, China. Electronic address: 709852011@qq.com. 5. Department of Nephrology, The Third Xiangya Hospital, Central South University, Changsha, Hunan Province, China. Electronic address: weizhangxy@126.com. 6. International Medicine Department, Ningbo First Hospital, Zhejiang University, Ningbo, China. Electronic address: stephen0726@163.com. 7. Department of Nephrology, The Third Xiangya Hospital, Central South University, Changsha, Hunan Province, China. Electronic address: aimei_lam@163.com. 8. Department of Nephrology, The Third Xiangya Hospital, Central South University, Changsha, Hunan Province, China. Electronic address: 790900598@163.com. 9. Department of Nephrology, The Third Xiangya Hospital, Central South University, Changsha, Hunan Province, China. Electronic address: 727803537@qq.com. 10. Department of Nephrology, The Third Xiangya Hospital, Central South University, Changsha, Hunan Province, China. Electronic address: wuxueqin@csu.edu.cn. 11. Department of Nutritional, Xiangya Hospital, Central South University, Changsha, Hunan Province, China. Electronic address: doctorzhangqin@163.com. 12. Department of Nephrology, The Third Xiangya Hospital, Central South University, Changsha, Hunan Province, China. Electronic address: jwwangdoc@163.com. 13. Department of Nephrology, The Third Xiangya Hospital, Central South University, Changsha, Hunan Province, China. Electronic address: zhanghaoliaoqing@163.com.
Abstract
OBJECTIVE: This study aimed to assess the effect and mechanism of SS31 on cisplatin-induced acute kidney injury (CP-AKI) both in vivo and in vitro. METHOD: Male mices and HK-2 cells were treated using cisplatin to establish models of CP-AKI. 32 C57BL/6 mices were randomly divided into four groups (control group, CP group, CP + normal saline group, CP + SS-31 group). Cisplatin was intraperitoneally injected once to the mice (25 mg/kg). SS31 was administrated for 10 days at dosages of 10 mg/kg per day. Kidney histological changes and level of reactive oxygen species(ROS) were detected. In vitro studies, HK-2 cells were incubated with cisplatin (50 u M) or combimed with SS-31(100 u M), the level of mitochondrial ROS, apoptosis rate and the the expression of NLRP3, Caspase-1 and IL-1β were tested. RESULTS: Renal tubulointerstitial apoptosis and oxidative stress were significantly increased in CP-AKI mice. Cisplatin caused elevation of serum creatinine (Scr), blood urea nitrogen (BUN) levels and enhanced IL-1β, caspase1 and NLRP3 expression, the electron microscopy examination showed mitochondria cristae swelling, mitochondrial spheres and partial ridge breakdown in renal tubular cell of CP-AKI mice. SS31 treatment could effectively suppress mitochondrial ROS, ameliorate these lesions and decrease the expression of NLRP3, IL-1β and Caspase1. In vitro studies, SS31 could restored the level of mitochondrial ROS and downregulate apoptosis rate in HK-2 cells, moreover, the elevated expression of NLRP3, IL-1β and Caspase-1were restored. CONCLUSION: SS31 could protect CP-AKI in mices, which might be due to an anti-oxidative and anti-apoptotic action via regulating mitochondrial ROS-NLRP3 pathway. NLRP3 inflammasome might be considered as a novel therapeutic target of CP-AKI.
OBJECTIVE: This study aimed to assess the effect and mechanism of SS31 on cisplatin-induced acute kidney injury (CP-AKI) both in vivo and in vitro. METHOD: Male mices and HK-2 cells were treated using cisplatin to establish models of CP-AKI. 32 C57BL/6 mices were randomly divided into four groups (control group, CP group, CP + normal saline group, CP + SS-31 group). Cisplatin was intraperitoneally injected once to the mice (25 mg/kg). SS31 was administrated for 10 days at dosages of 10 mg/kg per day. Kidney histological changes and level of reactive oxygen species(ROS) were detected. In vitro studies, HK-2 cells were incubated with cisplatin (50 u M) or combimed with SS-31(100 u M), the level of mitochondrial ROS, apoptosis rate and the the expression of NLRP3, Caspase-1 and IL-1β were tested. RESULTS: Renal tubulointerstitial apoptosis and oxidative stress were significantly increased in CP-AKI mice. Cisplatin caused elevation of serum creatinine (Scr), blood ureanitrogen (BUN) levels and enhanced IL-1β, caspase1 and NLRP3 expression, the electron microscopy examination showed mitochondria cristae swelling, mitochondrial spheres and partial ridge breakdown in renal tubular cell of CP-AKI mice. SS31 treatment could effectively suppress mitochondrial ROS, ameliorate these lesions and decrease the expression of NLRP3, IL-1β and Caspase1. In vitro studies, SS31 could restored the level of mitochondrial ROS and downregulate apoptosis rate in HK-2 cells, moreover, the elevated expression of NLRP3, IL-1β and Caspase-1were restored. CONCLUSION: SS31 could protect CP-AKI in mices, which might be due to an anti-oxidative and anti-apoptotic action via regulating mitochondrial ROS-NLRP3 pathway. NLRP3 inflammasome might be considered as a novel therapeutic target of CP-AKI.
Authors: Ana Karina Aranda-Rivera; Anjali Srivastava; Alfredo Cruz-Gregorio; José Pedraza-Chaverri; Shrikant R Mulay; Alexandra Scholze Journal: Antioxidants (Basel) Date: 2022-01-27