Xiaofei Peng1, Tao Yang2, Guoyong Liu3, Hong Liu4, Youming Peng4, Liyu He5. 1. Department of Rheumatology and Immunology, The Second Xiangya Hospital, Central South University, Changsha 410000, Hunan, PR China. 2. Department of Otolaryngology, Head and Neck Surgery, the Second Xiangya Hospital, Central South University, Changsha 410000, Hunan, PR China. 3. Department of Nephrology, The First Affiliated Hospital of Changde Vocational Technical College, Changde 415000, Hunan, PR China. 4. Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha 410000, Hunan, PR China. 5. Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha 410000, Hunan, PR China. Electronic address: heliyu1124@csu.edu.cn.
Abstract
BACKGROUND: Lupus nephritis (LN) is a leading cause of mortality. The activation of NLRP3 inflammasome contributed to LN development and thus became a therapeutic target. Here we assessed the therapeutic potential of piperine, a bioactive compound known to target NLRP3 inflammasome, on LN development both in vivo and in vitro. METHODS: LN was induced in BALB/c mice via intraperitoneal injection of pristane. Upon treatment with increasing doses of piperine, we assessed renal lesions, measured serum levels of pro-inflammatory cytokines, and examined expressions of key components of NLRP3 inflammasome in kidney. To explore the molecular mechanisms, we treated the proximal tubular epithelial HK-2 cells with lipopolysaccharide (LPS) and ATP, and examined the effects of piperine on pyroptosis and the activation of NLRP3 inflammasome. Furthermore, we assessed the significance of AMPK signaling in piperine functions in HK-2 cells. RESULTS: In pristane-injected mice, piperine significantly ameliorated LN development in a dose-dependent manner, which was associated with the inhibition of NLRP3 inflammasome and the reduction of serum IL-1β, but not of IL-18 level. In HK-2 cells, piperine potently inhibited pyroptosis and the activation of NLRP3 inflammasome in response to LPS + ATP. The effects of piperine were mediated by blocking AMPK activation, and the AMPK agonist metformin bypassed the activities of piperine, and resumed pyroptosis as well as the activation on NLRP3 inflammasome. CONCLUSIONS: By targeting AMPK, piperine significantly suppressed the activation of NLRP3 inflammasome, inhibited the release of pro-inflammatory cytokines, blocked the pyroptosis of tubular epithelial cells, and thus suppressed the development of LN.
BACKGROUND:Lupus nephritis (LN) is a leading cause of mortality. The activation of NLRP3 inflammasome contributed to LN development and thus became a therapeutic target. Here we assessed the therapeutic potential of piperine, a bioactive compound known to target NLRP3 inflammasome, on LN development both in vivo and in vitro. METHODS: LN was induced in BALB/c mice via intraperitoneal injection of pristane. Upon treatment with increasing doses of piperine, we assessed renal lesions, measured serum levels of pro-inflammatory cytokines, and examined expressions of key components of NLRP3 inflammasome in kidney. To explore the molecular mechanisms, we treated the proximal tubular epithelial HK-2 cells with lipopolysaccharide (LPS) and ATP, and examined the effects of piperine on pyroptosis and the activation of NLRP3 inflammasome. Furthermore, we assessed the significance of AMPK signaling in piperine functions in HK-2 cells. RESULTS: In pristane-injected mice, piperine significantly ameliorated LN development in a dose-dependent manner, which was associated with the inhibition of NLRP3 inflammasome and the reduction of serum IL-1β, but not of IL-18 level. In HK-2 cells, piperine potently inhibited pyroptosis and the activation of NLRP3 inflammasome in response to LPS + ATP. The effects of piperine were mediated by blocking AMPK activation, and the AMPK agonist metformin bypassed the activities of piperine, and resumed pyroptosis as well as the activation on NLRP3 inflammasome. CONCLUSIONS: By targeting AMPK, piperine significantly suppressed the activation of NLRP3 inflammasome, inhibited the release of pro-inflammatory cytokines, blocked the pyroptosis of tubular epithelial cells, and thus suppressed the development of LN.
Authors: Ke-Jia Zhang; Qi Wu; Shi-Min Jiang; Lei Ding; Chao-Xia Liu; Ming Xu; Ying Wang; Yao Zhou; Li Li Journal: Oxid Med Cell Longev Date: 2021-04-28 Impact factor: 6.543