LIGHT-HVEM/LTβR通路在顺铂诱导急性肾损伤中的作用机制研究

Cisplatin nephrotoxicity is an unavoidable and serious companion, yet effective treatment strategies remains limited. One of the more common presentations is acute kidney injury (AKI) which occurs in 25-35% of patients. It was believed that mitochondrial dysfunction of renal tubular epithelial cell and inflammatory response play an important role in Cis-AKI, but the underlying mechanism remains unclear. Moreover, several studies indicated that LIGHT is central to inflammation responses and cell destructions. In the previous studies, we found that LIGHT and its receptors expression were significantly increased in mouse kidneys treated with Cisplatin. Contrast to that, studies revealed that renal functions and tubular epithelial cell injury decreased dramatically in LIGHT gene knock-out mice. We therefore hypothesized that LIGHT signal pathway mediates the Cis-AKI initiation and progression via promoting tubular epithelial cell injury and inflammatory response. In this study, the effects and underlying mechanisms of LIGHT signal pathway in Cis-AKI will be deeply investigated and improvements conferred by blocking this pathway in in Cis-AKI will also be explored. Anticipative results will enhance our knowledge for the pathophysiology mechanisms of in Cis-AKI, which ultimately provide effective treatment strategies for Cis-AKI.

顺铂肾毒性是肿瘤化疗过程中无法避免的严重不良反应，约1/3化疗患者出现肾功能障碍导致急性肾损伤（Cis-AKI）。目前尚缺乏有效预防及治疗策略。肾小管上皮细胞线粒体损伤及免疫炎症反应是Cis-AKI的重要机制。作为一种重要的炎症因子，我们的前期研究发现：LIGHT及其受体HVEM/LTβR在小鼠Cis-AKI肾组织中表达显著增加；反之，LIGHT基因敲除后Cis-AKI则显著减轻，提示：LIGHT通路可能在Cis-AKI病理过程中发挥关键作用。本研究拟在首次发现LIGHT敲除可显著改善Cis-AKI基础上，通过体内外实验深入探讨LIGHT通路在Cis-AKI中的作用及机制；评价阻断该通路在改善Cis-AKI中的干预效果。预期研究结果不但可以加深对Cis-AKI病理生理机制的认识，并可为Cis-AKI临床治疗新策略发展提供重要的理论依据。

顺铂肾毒性是肿瘤化疗过程中无法避免的严重不良反应，约1/3化疗患者出现肾功能障碍.导致急性肾损伤（Cis-AKI）。目前尚缺乏有效预防及治疗策略。肾小管上皮细胞线粒体损伤.及免疫炎症反应是Cis-AKI的重要机制。作为一种重要的炎症因子，我们的前期研究发现：LIG.HT及其受体HVEM/LTβR在小鼠Cis-AKI肾组织中表达显著增加；反之，LIGHT基因敲除后Cis-AK.I则显著减轻，提示：LIGHT通路可能在Cis-AKI病理过程中发挥关键作用。本研究拟在首次发.现LIGHT敲除可显著改善Cis-AKI基础上，通过体内外实验深入探讨LIGHT通路在Cis-AKI中的作.用及机制；评价阻断该通路在改善Cis-AKI中的干预效果。预期研究结果不但可以加深对Cis-A.KI病理生理机制的认识，并可为Cis-AKI临床治疗新策略发展提供重要的理论依据。