Li Guangbi, Chen Zhida, Bhat Owais M, Zhang Qinghua, Abais-Battad Justine M, Conley Sabena M, Ritter Joseph K, Li Pin-Lan
Department of Pharmacology and Toxicology, School of Medicine, Virginia Commonwealth University, Richmond, VA.
Department of Pharmacology and Toxicology, School of Medicine, Virginia Commonwealth University, Richmond, VA
J Lipid Res. 2017 Jun;58(6):1080-1090. doi: 10.1194/jlr.M072587. Epub 2017 Apr 12.
The nucleotide-binding oligomerization domain-like receptor containing pyrin domain 3 (NLRP3) inflammasome has been implicated in podocyte injury and glomerular sclerosis during hyperhomocysteinemia (hHcys). However, it remains unclear whether the NLRP3 inflammasome can be a therapeutic target for treatment of hHcys-induced kidney injury. Given that DHA metabolites-resolvins have potent anti-inflammatory effects, the present study tested whether the prototype, resolvin D1 (RvD1), and 17S-hydroxy DHA (17S-HDHA), an intermediate product, abrogate hHcys-induced podocyte injury by targeting the NLRP3 inflammasome. In vitro, confocal microscopy demonstrated that 17S-HDHA (100 nM) and RvD1 (60 nM) prevented Hcys-induced formation of NLRP3 inflammasomes, as shown by reduced colocalization of NLRP3 with apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) or caspase-1. Both DHA metabolites inhibited Hcys-induced caspase-1 activation and interleukin-1β production. However, DHA had no significant effect on these Hcys-induced changes in podocytes. In vivo, DHA lipoxygenase metabolites substantially inhibited podocyte NLRP3 inflammasome formation and activation and consequent glomerular sclerosis in mice with hHcys. Mechanistically, RvD1 and 17S-HDHA were shown to suppress Hcys-induced formation of lipid raft redox signaling platforms and subsequent O production in podocytes. It is concluded that inhibition of NLRP3 inflammasome activation is one of the important mechanisms mediating the beneficial action of RvD1 and 17S-HDHA on Hcys-induced podocyte injury and glomerular sclerosis.
含吡啉结构域3的核苷酸结合寡聚化结构域样受体（NLRP3）炎性小体与高同型半胱氨酸血症（hHcys）期间的足细胞损伤和肾小球硬化有关。然而，NLRP3炎性小体是否可作为治疗hHcys诱导的肾损伤的治疗靶点仍不清楚。鉴于DHA代谢产物——消退素具有强大的抗炎作用，本研究测试了原型消退素D1（RvD1）和中间产物17S-羟基DHA（17S-HDHA）是否通过靶向NLRP3炎性小体来减轻hHcys诱导的足细胞损伤。在体外，共聚焦显微镜显示，17S-HDHA（100 nM）和RvD1（60 nM）可防止同型半胱氨酸（Hcys）诱导的NLRP3炎性小体形成，NLRP3与含半胱天冬酶募集结构域的凋亡相关斑点样蛋白（ASC）或半胱天冬酶-1的共定位减少表明了这一点。两种DHA代谢产物均抑制Hcys诱导的半胱天冬酶-1激活和白细胞介素-1β产生。然而，DHA对足细胞中这些Hcys诱导的变化没有显著影响。在体内，DHA脂氧合酶代谢产物可显著抑制hHcys小鼠足细胞NLRP3炎性小体的形成和激活以及随之而来的肾小球硬化。从机制上讲，RvD1和17S-HDHA可抑制Hcys诱导的脂筏氧化还原信号平台的形成以及足细胞中随后的氧产生。结论是，抑制NLRP3炎性小体激活是介导RvD1和17S-HDHA对Hcys诱导的足细胞损伤和肾小球硬化有益作用的重要机制之一。
