The Mechanism of Delayed Ischemic Preconditioning in Alleviating Acute Ischemia/Reperfusion Renal Injury through Treg Mediated by Immature CD11c(+) Dendritic Cells.
The Mechanism of Delayed Ischemic Preconditioning in Alleviating Acute Ischemia/Reperfusion Renal Injury through Treg Mediated by Immature CD11c(+) Dendritic Cells.
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未成熟CD11c树突状细胞介导的Treg延迟缺血预处理减轻急性缺血/再灌注肾损伤的机制
DOI：
10.1159/000527172
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发表时间：
2022-12
期刊：
影响因子：
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中科院分区：
文献类型：
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肾缺血再灌注损伤(IRI)是急性肾损伤的主要原因之一，其机制复杂，涉及多因素，而延迟性缺血预适应(DIPC)对此过程具有保护作用。我们在前期的研究中发现，DIPC通过抑制树突状细胞(DCs)的成熟发挥对肾脏IRI的保护作用，但其机制尚不清楚。本研究旨在探讨DIPC通过未成熟树突状细胞(ImDC)介导的Treg对小鼠肾脏IRI的保护作用机制。采用IRI小鼠模型、DIPC治疗和CD11c+DCs(CD11c-DTR)基因敲除小鼠进行研究。用流式细胞仪分析肾、脾中DC和Treg细胞的成熟分化情况。用HE染色观察肾组织病理改变。测定血清肌酐、氧化应激因子(超氧化物歧化酶、丙二醛)和炎症因子(肿瘤坏死因子-α、IL-10、IL-4)水平。然后，将imDC与HK-2细胞共同培养，用流式细胞仪和PI-Hoechst 33,342荧光染色检测细胞在缺氧/复氧(H/R)条件下的凋亡率。DIPC可降低肾脏肌酐水平，减轻肾脏病理损害，减轻IRI所致的氧化应激和炎症反应。此外，DIPC可减少肾组织中成熟DC(MDCs)的数量，增加Treg淋巴细胞的浸润，而DC的减少则逆转了这一过程。此外，我们的体外实验发现，在H/R模型中，与imDC共同培养的HK-2细胞的凋亡率减少。DIPC可以调节DC向imDC的分化，从而影响Treg细胞的分化水平和分布，从而发挥其对肾脏IRI的保护作用。
Renal ischemia-reperfusion injury (IRI) is one of the major causes of acute kidney injury, and its mechanism is complex involving multiple factors, while delayed ischemic preconditioning (DIPC) has a protective effect on the above process. In our previous study, we found that DIPC can exert its protection on renal IRI by inhibiting the maturation of dendritic cells (DCs), but the mechanism has not been clarified. This study aimed to investigate the protective mechanism of DIPC on renal IRI in mice through Treg mediated by immature DCs (imDCs). The IRI mice model, DIPC treatment, and conditional CD11c<sup>+</sup> DCs (CD11c-DTR) knockout mice were used to perform our study. The maturation and differentiation of DCs and Treg cells in the kidney and spleen were analyzed by flow cytometry. HE staining was used to evaluate the pathology of the kidney tissue. The level of creatinine (Cr), oxidative stress factors (SOD, MDA), and inflammatory factors (TNF-α, IL-10, IL-4) were also measured. Then, imDCs were co-cultured with HK-2 cells, and apoptosis was analyzed with flow cytometry and PI-Hoechst 33,342 fluorescence staining to assess the apoptosis rate of HK-2 cells under hypoxic-reoxygenated (H/R) conditions. DIPC could decrease renal Cr levels, alleviate pathological renal damage, and reduce oxidative stress and inflammation caused by IRI. Moreover, DIPC could decrease the number of mature DCs (mDCs) and increase Treg lymphocyte infiltration in the kidney tissue, while the reduction of DCs reversed this process. In addition, our in vitro experiment found that in the H/R model, the apoptosis of HK-2 cells decreased which were co-cultured with imDCs. DIPC can regulate the differentiation of DCs into imDCs, thus affecting the differentiation level and distribution of Treg cells to exert its protective effect on renal IRI.
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