Division of Nephrology, Department of Medicine, Johns Hopkins University School of Medicine, Ross Bldg., Rm. 965, 720 Rutland Ave., Baltimore, MD 21205, USA.
Am J Physiol Renal Physiol. 2012 Mar 15;302(6):F762-73. doi: 10.1152/ajprenal.00335.2011. Epub 2011 Dec 7.
Although T cells have been shown to play a direct role in kidney ischemia-reperfusion injury (IRI), little is known about the underlying mechanisms. We hypothesized that studying the transcriptional responses in kidney-infiltrating T cells would help elucidate novel therapeutic targets for kidney IRI. Unilateral renal pedicle clamping for 45 min was performed in male C57BL/6 mice, and CD3(+) T cells were isolated from the kidney and purified. Transcriptional activities of T cell were measured by array-based PCR compared between ischemic kidneys and contralateral nonischemic kidneys. Among total of 89 genes analyzed, 24, 22, 24, and 37 genes were significantly changed at 6 h, day 3, day 10, and day 28 after IRI. Genes associated with cytokines, chemokines, and costimulatory molecules were upregulated. Pathway analysis identified CC motif chemokine receptor 5 (CCR5) as a candidate pathophysiological pathway. CCR5 upregulation was validated at the protein level, and CCR5 blockade improved renal function after kidney IRI. Using discovery techniques to identify transcriptional responses in purified kidney-infiltrating cells enabled the elucidation of novel mechanisms and therapeutic targets for IRI.
尽管已经证明 T 细胞在肾缺血再灌注损伤（IRI）中发挥直接作用，但对于其潜在机制知之甚少。我们假设研究肾浸润 T 细胞中的转录反应将有助于阐明肾 IRI 的新治疗靶点。在雄性 C57BL/6 小鼠中进行单侧肾蒂夹闭 45 分钟，并从肾脏中分离出 CD3(+)T 细胞并进行纯化。通过基于阵列的 PCR 比较缺血肾和对侧非缺血肾之间的 T 细胞转录活性。在分析的总共 89 个基因中，24、22、24 和 37 个基因在 IRI 后 6 小时、第 3 天、第 10 天和第 28 天显着变化。与细胞因子、趋化因子和共刺激分子相关的基因上调。途径分析确定 C 型趋化因子受体 5（CCR5）为候选病理生理途径。在蛋白质水平验证了 CCR5 的上调，并且 CCR5 阻断可改善肾 IRI 后的肾功能。使用发现技术鉴定纯化的肾浸润细胞中的转录反应，可阐明 IRI 的新机制和治疗靶点。
