Angiopoietin-like 4 (ANGPTL4) Suppression Ameliorates Lupus Nephritis in MRL/lpr Mice by Inactivating NLRP3 Inflammasome and Inhibiting Inflammatory Response.

IF 1.1 4区医学 Q4 IMMUNOLOGY

Iranian Journal of Immunology Pub Date : 2023-09-01 DOI:10.22034/iji.2023.97942.2541

Dan Luo, Jun Li, Manli Hu, You Wang, Pei Pi, Min Ning, Jun Wu

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Abstract

Background: Lupus nephritis (LN) refers to the injury caused by systemic lupus erythematosus (SLE) involving the kidneys. A previous study identified angiopoietin-like protein 4 (ANGPTL4) as a novel urinary biomarker for tracking disease activity in LN.

Objective: To investigate the detailed role and regulatory mechanism of ANGPTL4 in experimental models of LN.

Methods: MRL/lpr mice 11-week-old were injected with adeno-associated virus (AAV)-mediated ANGPTL4 short hairpin RNA (shRNA). At 16 and 20 weeks of age, 24-h urine samples were harvested to measure proteinuria levels. After the mice were sacrificed, blood and kidney tissues were harvested to examine serum creatinine (cr) and blood urea nitrogen (BUN) levels, kidney histological changes, and pro-inflammatory cytokine production. Additionally, the levels of NLRP3 inflammasome-associated molecules in mouse renal tissues were detected to clarify the underlying mechanism.

Results: The AAV-sh-ANGPTL4 injection significantly reduced the proteinuria, cr, and BUN levels in MRL/lpr mice. ANGPTL4 silencing ameliorated glomerular, tubular, and interstitial damage in mice, mitigating the pathological alternations of LN. In addition, ANGPTL4 knockdown repressed pro-inflammatory cytokine production in the kidneys. Mechanically, ANGPTL4 suppression inhibited NLRP3 inflammasome expression in renal tissues of mice.

Conclusion: ANGPTL4 silencing inhibits the NLRP3 inflammasome-mediated inflammatory response, thereby ameliorating LN in MRL/lpr mice.

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抑制血管生成素样 4 (ANGPTL4) 可使 NLRP3 炎症小体失活并抑制炎症反应，从而改善 MRL/lpr 小鼠的狼疮肾炎。

背景：狼疮肾炎（LN）是指由系统性红斑狼疮（SLE）引起的涉及肾脏的损伤。先前的一项研究发现血管生成素样蛋白4（ANGPTL4）是追踪狼疮性肾炎疾病活动的新型尿液生物标记物：研究 ANGPTL4 在 LN 实验模型中的详细作用和调控机制：方法：给11周龄的MRL/lpr小鼠注射腺相关病毒（AAV）介导的ANGPTL4短发夹RNA（shRNA）。在小鼠 16 周龄和 20 周龄时，采集其 24 小时尿液样本以测量蛋白尿水平。小鼠被处死后，采集血液和肾脏组织以检测血清肌酐（cr）和血尿素氮（BUN）水平、肾脏组织学变化以及促炎细胞因子的产生。此外，还检测了小鼠肾组织中 NLRP3 炎症体相关分子的水平，以明确其潜在机制：结果：注射AAV-sh-ANGPTL4能显著降低MRL/lpr小鼠的蛋白尿、cr和BUN水平。沉默 ANGPTL4 可改善小鼠肾小球、肾小管和肾间质损伤，减轻 LN 的病理变化。此外，ANGPTL4 基因敲除抑制了肾脏中促炎细胞因子的产生。从机制上讲，ANGPTL4抑制抑制了小鼠肾组织中NLRP3炎性体的表达：结论：抑制 ANGPTL4 可抑制 NLRP3 炎性体介导的炎症反应，从而改善 MRL/lpr 小鼠的 LN。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Iranian Journal of Immunology Medicine-Immunology and Allergy

CiteScore

1.60

自引率

0.00%

发文量

审稿时长

12 weeks

期刊介绍： The Iranian Journal of Immunology (I.J.I) is an internationally disseminated peer-reviewed publication and publishes a broad range of experimental and theoretical studies concerned with all aspects of immunology.