当前位置: X-MOL 学术J. Immunol. › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
CD4+ T Cell–Derived NGAL Modifies the Outcome of Ischemic Acute Kidney Injury
The Journal of Immunology ( IF 4.4 ) Pub Date : 2019-12-30 , DOI: 10.4049/jimmunol.1900677
Sul A Lee 1 , Sanjeev Noel 1 , Johanna T Kurzhagen 1 , Mohanraj Sadasivam 2 , Phillip M Pierorazio 3 , Lois J Arend 2 , Abdel R Hamad 2 , Hamid Rabb 4
Affiliation  

Key Points Kidney CD4 T cells significantly increase Lcn2/NGAL expression following IR injury. CD4 T cell Lcn2/NGAL protects against IR-induced AKI. Lcn2 expression increased in ischemic CD4 T cells from human kidney. Visual Abstract CD4+ T cells mediate the pathogenesis of ischemic and nephrotoxic acute kidney injury (AKI). However, the underlying mechanisms of CD4+ T cell–mediated pathogenesis are largely unknown. We therefore conducted unbiased RNA-sequencing to discover novel mechanistic pathways of kidney CD4+ T cells after ischemia compared with normal mouse kidney. Unexpectedly, the lipocalin-2 (Lcn2) gene, which encodes neutrophil gelatinase-associated lipocalin (NGAL) had the highest fold increase (∼60). The NGAL increase in CD4+ T cells during AKI was confirmed at the mRNA level with quantitative real-time PCR and at the protein level with ELISA. NGAL is a potential biomarker for the early detection of AKI and has multiple potential biological functions. However, the role of NGAL produced by CD4+ T cells is not known. We found that ischemic AKI in NGAL knockout (KO) mice had worse renal outcomes compared with wild-type (WT) mice. Adoptive transfer of NGAL-deficient CD4+ T cells from NGAL KO mice into CD4 KO or WT mice led to worse renal function than transfer of WT CD4+ T cells. In vitro–simulated ischemia/reperfusion showed that NGAL-deficient CD4+ T cells express higher levels of IFN-γ mRNA compared with WT CD4+ T cells. In vitro differentiation of naive CD4+ T cells to Th17, Th1, and Th2 cells led to significant increase in Lcn2 expression. Human kidney CD4+ T cell NGAL also increased significantly after ischemia. These results demonstrate an important role for CD4+ T cell NGAL as a mechanism by which CD4+ T cells mediate AKI and extend the importance of NGAL in AKI beyond diagnostics.

中文翻译:

CD4+ T 细胞衍生的 NGAL 改变缺血性急性肾损伤的结果

关键点肾 CD4 T 细胞在 IR 损伤后显着增加 Lcn2/NGAL 表达。CD4 T 细胞 Lcn2/NGAL 可防止 IR 诱导的 AKI。Lcn2 表达在来自人肾脏的缺血性 CD4 T 细胞中增加。视觉摘要 CD4+ T 细胞介导缺血性和肾毒性急性肾损伤 (AKI) 的发病机制。然而,CD4+ T 细胞介导的发病机制的潜在机制在很大程度上是未知的。因此,我们进行了无偏 RNA 测序,以发现与正常小鼠肾脏相比缺血后肾脏 CD4+ T 细胞的新机制途径。出乎意料的是,编码中性粒细胞明胶酶相关脂质运载蛋白(NGAL)的脂质运载蛋白-2(Lcn2)基因的倍数增加最高(~60)。AKI 期间 CD4+ T 细胞中 NGAL 的增加通过定量实时 PCR 在 mRNA 水平和通过 ELISA 在蛋白质水平得到证实。NGAL 是 AKI 早期检测的潜在生物标志物,具有多种潜在的生物学功能。然而,CD4+ T 细胞产生的 NGAL 的作用尚不清楚。我们发现与野生型 (WT) 小鼠相比,NGAL 敲除 (KO) 小鼠的缺血性 AKI 具有更差的肾脏结果。将 NGAL 缺陷型 CD4+ T 细胞从 NGAL KO 小鼠过继转移到 CD4 KO 或 WT 小鼠中导致肾功能比转移 WT CD4+ T 细胞更差。体外模拟的缺血/再灌注表明,与 WT CD4+ T 细胞相比,NGAL 缺陷型 CD4+ T 细胞表达更高水平的 IFN-γ mRNA。幼稚 CD4+ T 细胞体外分化为 Th17、Th1 和 Th2 细胞导致 Lcn2 表达显着增加。缺血后人肾 CD4+ T 细胞 NGAL 也显着增加。这些结果证明了 CD4+ T 细胞 NGAL 作为 CD4+ T 细胞介导 AKI 并将 NGAL 在 AKI 中的重要性扩展到诊断之外的机制的重要作用。
更新日期:2019-12-30
down
wechat
bug