Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai, China.
Clinical Center for Sleep Breathing Disorder and Snoring, Zhongshan Hospital, Fudan University, Shanghai, China.
J Cell Physiol. 2018 Dec;233(12):9404-9415. doi: 10.1002/jcp.26784. Epub 2018 Jun 28.
Chronic intermittent hypoxia (CIH), as the foremost pathophysiological change of obstructive sleep apnea (OSA), contributes to continued deterioration in renal function. Nucleotide-binding domain like receptor protein 3 (NLRP3) inflammasome is a multiprotein complex that triggers innate immune responses to infection and cell stress through activation of caspase-1 and maturation of inflammatory pro-interleukin-1β cytokine. Emerging evidence indicates that inhibition of the NLRP3 inflammasome ameliorates renal injury. Nevertheless, it is uncertain whether NLRP3 inflammasome participates in CIH-induced renal injury. The molecular mechanisms modulating NLRP3 inflammasome activation remain to be elucidated. Compared with wild-type mice, NLRP3 knockout mice dramatically protected them from kidney injury, as indicated by the restoration of creatinine levels, lessened histopathological alterations, and the suppression of macrophages infiltration stained with F4/80. NLRP3 deficiency notably reversed CIH-induced oxidative stress (malondialdehyde and superoxide dismutase), concomitantly with the abrogated apoptosis-related proteins and proinflammatory signaling pathway. Consistently, NLRP3-deficient tubular cells remarkably inhibited reactive oxygen species generation and NLRP3 inflammasome activation. Furthermore, our study revealed that microRNA-155 (miR-155) was augmented in the renal tissue and HK-2 cells exposed to CIH. In addition, we investigated the role of miR-155 in the regulation of NLRP3 inflammasome. Inhibition of miR-155 suppressed the CIH-induced NLRP3 inflammasome activation in renal tubular cells, whereas overexpression of miR-155 promoted oxidation and enhanced NLRP3 pathway. Collectively, we demonstrated that miR-155 might be a positive-regulator of NLRP3 pathway by inhibiting the targeted FOXO3a gene. These results established a link between the miR-155/FOXO3a pathway and the NLRP3 inflammasome, suggesting pharmacological blockage of NLRP3 as a potential therapeutic strategy for OSA-associated chronic kidney disease.
慢性间歇性低氧（CIH）作为阻塞性睡眠呼吸暂停（OSA）的主要病理生理改变，导致肾功能持续恶化。核苷酸结合域样受体蛋白 3（NLRP3）炎性小体是一种多蛋白复合物，通过激活半胱天冬酶-1 和成熟炎症前白细胞介素-1β细胞因子，引发固有免疫反应对抗感染和细胞应激。新出现的证据表明，抑制 NLRP3 炎性小体可改善肾脏损伤。然而，尚不确定 NLRP3 炎性小体是否参与 CIH 诱导的肾脏损伤。调节 NLRP3 炎性小体激活的分子机制仍有待阐明。与野生型小鼠相比，NLRP3 敲除小鼠明显保护它们免受肾脏损伤，表现在肌酐水平的恢复、组织病理学改变的减轻以及 F4/80 染色的巨噬细胞浸润的抑制。NLRP3 缺乏显著逆转 CIH 诱导的氧化应激（丙二醛和超氧化物歧化酶），同时伴随着凋亡相关蛋白和促炎信号通路的阻断。一致地，NLRP3 缺陷的肾小管细胞显著抑制活性氧生成和 NLRP3 炎性小体激活。此外，我们的研究表明，微小 RNA-155（miR-155）在暴露于 CIH 的肾脏组织和 HK-2 细胞中增加。此外，我们研究了 miR-155 在调节 NLRP3 炎性小体中的作用。抑制 miR-155 可抑制肾小管细胞中 CIH 诱导的 NLRP3 炎性小体激活，而过表达 miR-155 则促进氧化并增强 NLRP3 途径。总的来说，我们证明 miR-155 通过抑制靶向 FOXO3a 基因可能成为 NLRP3 途径的正调节剂。这些结果建立了 miR-155/FOXO3a 途径与 NLRP3 炎性小体之间的联系，表明抑制 NLRP3 可能是治疗 OSA 相关慢性肾脏病的潜在治疗策略。
