LncRNA-HOTAIR promotes endothelial cell pyroptosis by regulating the miR-22/NLRP3 axis in hyperuricaemia.
LncRNA-HOTAIR promotes endothelial cell pyroptosis by regulating the miR-22/NLRP3 axis in hyperuricaemia.
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LncRNA-HOTAIR通过调节高尿酸血症中的miR-22/NLRP3轴促进内皮细胞焦亡
DOI：
10.1111/jcmm.16812
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发表时间：
2021-09
影响因子：
5.3
通讯作者：
Hong Q
中科院分区：
文献类型：
--
作者：
Chi K;Geng X;Liu C;Zhang Y;Cui J;Cai G;Chen X;Wang F;Hong Q
长链非编码RNA（lncRNA）在高尿酸血症引发的肾脏炎症反应中发挥着重要作用。然而，lncRNA参与高尿酸血症诱导的内皮损伤的潜在分子机制仍不明确。在本研究中，我们探究了lncRNA - HOTAIR在高浓度尿酸（HUA）诱导的肾损伤中的调控作用。我们建立了高尿酸血症小鼠模型以及体外尿酸（UA）诱导的人脐静脉内皮细胞（HUVEC）损伤模型。在HUA处理的HUVEC细胞和高尿酸血症小鼠中，我们观察到HOTAIR表达增加，而miR - 22表达降低。细胞焦亡相关蛋白（NLRP3、半胱天冬酶 - 1、GSDMD - N、GSDMD - FL）的表达增加。细胞培养上清液以及模型小鼠血清中乳酸脱氢酶（LDH）、白细胞介素 - 1β（IL - 1β）和白细胞介素 - 18（IL - 18）的释放也有所增加。HUA刺激的HUVEC细胞增殖受到显著抑制，且高尿酸血症小鼠肾脏中TUNEL阳性细胞数量增多。生物信息学分析、荧光素酶报告基因实验和RNA免疫沉淀（RIP）实验证实，HOTAIR通过竞争性结合miR - 22促进NLRP3炎性小体激活。在功能获得或缺失实验中，我们发现HOTAIR和NLRP3过表达或miR - 22敲低可激活HUA处理的HUVEC细胞中的NLRP3炎性小体并促进细胞焦亡，而NLRP3和HOTAIR敲低或miR - 22模拟物则产生相反的效果。此外，体内实验验证了HOTAIR敲低可减轻高尿酸血症小鼠的肾脏炎症。总之，我们证明在高尿酸血症中，lncRNA - HOTAIR通过竞争性结合miR - 22来调节NLRP3的表达，从而促进内皮细胞焦亡。
Long non‐coding RNA (lncRNA) plays an important role in the renal inflammatory response caused by hyperuricaemia. However, the underlying molecular mechanisms through which lncRNA is involved in endothelial injury induced by hyperuricaemia remain unclear. In this study, we investigated the regulatory role of lncRNA‐HOTAIR in high concentration of uric acid (HUA)–induced renal injury. We established hyperuricaemia mouse model and an in vitro uric acid (UA)–induced human umbilical vein endothelial cell (HUVEC) injury model. In HUA‐treated HUVECs and hyperuricaemia mice, we observed increased HOTAIR and decreased miR‐22 expression. The expression of pyroptosis‐associated protein (NLRP3, Caspase‐1, GSDMD‐N, GSDMD‐FL) was increased. The release of LDH, IL‐1β and IL‐18 in cell supernatants and the sera of model mice was also increased. The proliferation of HUVECs stimulated by HUA was significantly inhibited, and the number of TUNEL‐positive cells in hyperuricaemia mouse kidney was increased. Bioinformatics analysis and luciferase reporter and RIP assays confirmed that HOTAIR promoted NLRP3 inflammasome activation by competitively binding miR‐22. In gain‐ or loss‐of‐function experiments, we found that HOTAIR and NLRP3 overexpression or miR‐22 knock down activated the NLRP3 inflammasome and promoted pyroptosis in HUA‐treated HUVECs, while NLRP3 and HOTAIR knockdown or a miR‐22 mimic exerted the opposite effects. Furthermore, in vivo experiments validated that HOTAIR knockdown alleviated renal inflammation in hyperuricaemia mice. In conclusion, we demonstrated that in hyperuricaemia, lncRNA‐HOTAIR promotes endothelial cell pyroptosis by competitively binding miR‐22 to regulate NLRP3 expression.
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影响因子：
7
作者：
Place DE;Kanneganti TD
通讯作者：
Kanneganti TD
影响因子：
14.9
作者：
Moran VA;Perera RJ;Khalil AM
通讯作者：
Khalil AM
影响因子：
11.2
作者：
Battistelli C;Garbo S;Riccioni V;Montaldo C;Santangelo L;Vandelli A;Strippoli R;Tartaglia GG;Tripodi M;Cicchini C
通讯作者：
Cicchini C
影响因子：
30.5
作者：
通讯作者：
--
影响因子：
--
作者：
Fazi B;Garbo S;Toschi N;Mangiola A;Lombari M;Sicari D;Battistelli C;Galardi S;Michienzi A;Trevisi G;Harari-Steinfeld R;Cicchini C;Ciafrè SA
通讯作者：
Ciafrè SA