D-Ribose Induces Podocyte NLRP3 Inflammasome Activation and Glomerular Injury via AGEs/RAGE Pathway
D-Ribose Induces Podocyte NLRP3 Inflammasome Activation and Glomerular Injury via AGEs/RAGE Pathway
复制标题
D-核糖通过 AGEs/RAGE 途径诱导足细胞 NLRP3 炎症小体激活和肾小球损伤
DOI：
10.3389/fcell.2019.00259
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发表时间：
2019-10-30
影响因子：
5.5
通讯作者：
Li, Pin-Lan
中科院分区：
文献类型：
--
作者：
Hong, Jinni;Li, Guangbi;Li, Pin-Lan
D-核糖水平在II型糖尿病中被证明是增加的，并且增加的血液D-核糖涉及糖尿病并发症如糖尿病脑病和肾病的发展。然而，介导D-核糖在肾病中的致病作用的机制仍然知之甚少。鉴于D-核糖被报道诱导晚期糖基化终产物（AGEs）形成，本研究测试D-核糖是否通过AGEs/AGEs受体（AGEs）信号通路诱导NLRP 3活化和相关的肾小球损伤。在体内，C57 BL/6 J和Asc-/-小鼠用D-核糖处理，有或没有AGEs抑制剂。发现每天给予D-核糖30天诱导肾小球足细胞中NLRP 3炎性小体形成，如通过增加NLRP 3与包含半胱天冬酶募集结构域（ASC）或半胱天冬酶-1的阿尔茨海默病相关斑点样蛋白的共定位所示。这种D-核糖诱导的NLRP 3炎性体形成伴随着其活化，如通过增加的IL-1β产生（NLRP 3炎性体的主要产物）所证明的。对应于NLRP 3炎性体激活，D-核糖导致小鼠中显著的肾小球损伤。Asc基因缺失可明显减轻D-核糖诱导的肾小球炎性小体及相关病理改变。此外，发现接受D-核糖的小鼠肾小球中AGEs和AGEs的积累增加。在细胞研究中，我们还证实了D-核糖诱导足细胞中NLRP 3炎性小体的形成和活化，这被caspase-1抑制剂YvAD显著阻断。从机制上讲，AGEs形成抑制和β-D-核糖基因的切割或沉默可抑制D-核糖诱导的NLRP 3炎性体的形成和激活，如NLRP 3炎性体分子聚集、caspase-1活性和IL-1β产生的显著减少所示。这些结果有力地表明，相对长时间的D-核糖给药通过AGEs/β-内酰胺酶信号通路诱导足细胞NLRP 3炎性小体的形成和激活，这可能是导致糖尿病肾病的重要触发机制之一。
D-ribose levels are demonstrated to be increased in type II diabetes mellitus and increased blood D-ribose is involved in the development of diabetic complications such as diabetic encephalopathy and nephropathy. However, the mechanism mediating the pathogenic role of D-ribose in nephropathy remains poorly understood. Given that D-ribose was reported to induce advanced glycation end products (AGEs) formation, the present study tested whether D-ribose induces NLRP3 activation and associated glomerular injury via AGEs/receptor of AGEs (RAGE) signaling pathway. In vivo, C57BL/6J and Asc–/– mice were treated with D-ribose with or without AGEs inhibitor. Administration of D-ribose daily for 30 days was found to induce NLRP3 inflammasome formation in glomerular podocyte, as shown by increased co-localization of NLRP3 with apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) or caspase-1. This D-ribose-induced NLRP3 inflammasome formation was accompanied by its activation as evidenced by increased IL-1β production, a major product of NLRP3 inflammasome. Corresponding to NLRP3 inflammasome activation, D-ribose led to significant glomerular injury in mice. All these D-ribose-induced glomerular inflammasome and associated pathological changes were markedly attenuated by deletion of Asc gene. Furthermore, the accumulation of AGEs and RAGE was found increased in glomeruli of mice receiving D-ribose. In cell studies, we also confirmed that D-ribose induced NLRP3 inflammasome formation and activation in podocytes, which was significantly blocked by caspase-1 inhibitor, YvAD. Mechanically, AGEs formation inhibition and cleavage or silencing of RAGE gene were shown to suppress D-ribose-induced NLRP3 inflammasome formation and activation, as shown by significant reduction of NLRP3 inflammasome molecular aggregation, caspase-1 activity and IL-1β production. These results strongly suggest that relatively long term administration of D-ribose induces NLRP3 inflammasome formation and activation in podocytes via AGEs/RAGE signaling pathway, which may be one of important triggering mechanisms leading to diabetic nephropathy.