LIGHT-HVEM/LTβR通路在缺血再灌注肾损伤中的作用及机制研究

Renal ischemia/reperfusion injury (IRI) is an unavoidable event during kidney transplantation，which is one of the critical causes that lead to graft rejection. There isn't an effective treatment strategy for patients with renal IRI. Numerous studies have revealed that inflammatory processes mediated by the immune system are crucial in mediating renal injury, yet the underlying mechanism remains unclear. In the previous studies, we found that LIGHT and its receptors HVEM/LTβR were remarkably increased in mice with IRI. In contrast, renal injury was dramatically decreased in LIGHT gene knock-out mice, compared to the wild-type (WT) mice. We therefore hypothesized that LIGHT pathway may play a vital role in renal IRI. In the present studies, we will define the underlying mechanisms of LIGHT pathway in renal IRI in vivo and in vitro experiments, and then further explore the improvements conferred by blocking this pathway. Anticipative results will deep our knowledge for the pathophysiology mechanisms of renal IRI, which ultimately pave the way for novel treatment strategies for this clinic disease.

缺血再灌注肾损伤是导致移植排斥的重要原因，目前临床尚缺乏有效的治愈方法。免疫炎症是介导缺血再灌注肾损伤的主要因素。作为一种重要的促炎因子，我们前期结果发现：共刺激分子LIGHT及其受体HVEM和LTβR在小鼠缺血再灌注损伤肾组织中表达显著升高；反之，LIGHT基因缺陷缺血再灌注肾损伤则显著降低，提示：LIGHT通路可能在缺血再灌注肾损伤的病理发生中发挥关键作用。本研究拟在我们首次发现LIGHT缺陷可显著改善缺血再灌注肾损伤的基础上，通过体内外实验进一步探讨LIGHT通路介导缺血再灌注肾损伤的作用机制；评价阻断LIGHT通路在缺血再灌注肾损伤中的干预效果及其作用受体。预期结果不但有助于缺血再灌注肾损伤免疫病理机制的阐明，并可为缺血再灌注肾损伤临床治疗新策略的发展提供重要的理论依据。

缺血再灌注肾损伤是移植过程难以避免的事件，也是导致移植排斥的重要原因，目前临床尚缺乏有效的治愈方法。已知免疫炎症是介导缺血再灌注肾损伤的主要因素，但潜在机制不清楚。在本研究中，我们通过建立体内缺血再灌注肾损伤模型，研究了免疫炎症分子LIGHT和其受体HVEM/LTβR在缺血再灌注肾损伤病理发生中的作用，并探讨了其可能的作用机制。结果发现，LIGHT基因缺陷或阻断LIGHT通路对小鼠缺血再灌注肾损伤具有保护作用，并可在小鼠遭受严重的肾脏缺血再灌注损伤后有效防止其损伤肾脏向慢性纤维化肾病发展，提示LIGHT-LTR/HVEM途径在肾脏缺血再灌注损伤中起着重要的作用。进一步的研究发现，与WT小鼠相比，LIGHT缺陷小鼠肾脏缺血再灌注后肾组织局部中性粒细胞与单核细胞的浸润程度减轻，炎症因子和趋化因子的表达水平下降；凋亡的肾小管上皮细胞数目较WT小鼠减少，抗凋亡分子Bcl2的表达上调而促凋亡分子Bax表达下调；加入外源性rhLIGHT可促进缺氧再供氧介导的肾小管上皮细胞HK-2凋亡。这些结果表明LIGHT-LTR/HVEM途径在肾脏缺血再灌注损伤中起着重要的作用，LIGHT可能通过促进免疫炎症反应和肾小管细胞凋亡介导缺血再灌注肾损伤的病理发生，但更多的直接证据仍在进一步的探讨中。已有研究结果不但有助于缺血再灌注肾损伤免疫病理机制的阐明，并可为缺血再灌注肾损伤临床治疗新策略的发展提供重要的理论依据。