Semaphorin 3A inactivation suppresses ischemia-reperfusion-induced inflammation and acute kidney injury
Semaphorin 3A inactivation suppresses ischemia-reperfusion-induced inflammation and acute kidney injury
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DOI：
10.1152/ajprenal.00177.2014
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发表时间：
2014-07-15
影响因子：
4.2
通讯作者：
Ramesh, Ganesan
中科院分区：
文献类型：
--
作者：
Ranganathan, Punithavathi;Jayakumar, Calpurnia;Ramesh, Ganesan
最近的研究表明，已知在发育过程中调节细胞迁移的导向分子也可能在成人病理生理状态中发挥重要作用。一种这样的分子，semaphorin3A（sema3A），在小鼠和人类急性肾损伤（阿基）后高度表达，但其病理生理作用尚不清楚。sema3A基因失活保护小鼠免受缺血再灌注诱导的阿基，改善组织组织学，减少中性粒细胞浸润，防止上皮细胞凋亡，并增加尿液中细胞因子和趋化因子的排泄。基于药理学的sema3A受体结合抑制同样可防止缺血再灌注诱导的阿基。在体外，sema3A增强了上皮细胞、巨噬细胞和树突状细胞中toll样受体4介导的炎症。此外，给予sema3A处理的骨髓来源的树突状细胞加重了肾损伤。最后，sema3A通过表达DFFA样效应子a（cidea）增强顺铂诱导的体外肾上皮细胞凋亡。我们的数据表明，导向分子sema3A通过促进炎症和上皮细胞凋亡而加重阿基。
Recent studies show that guidance molecules that are known to regulate cell migration during development may also play an important role in adult pathophysiologic states. One such molecule, semaphorin3A (sema3A), is highly expressed after acute kidney injury (AKI) in mice and humans, but its pathophysiological role is unknown. Genetic inactivation of sema3A protected mice from ischemia-reperfusion-induced AKI, improved tissue histology, reduced neutrophil infiltration, prevented epithelial cell apoptosis, and increased cytokine and chemokine excretion in urine. Pharmacological-based inhibition of sema3A receptor binding likewise protected against ischemia-reperfusion-induced AKI. In vitro, sema3A enhanced toll-like receptor 4-mediated inflammation in epithelial cells, macrophages, and dendritic cells. Moreover, administration of sema3A-treated, bone marrow-derived dendritic cells exacerbated kidney injury. Finally, sema3A augmented cisplatin-induced apoptosis in kidney epithelial cells in vitro via expression of DFFA-like effector a (cidea). Our data suggest that the guidance molecule sema3A exacerbates AKI via promoting inflammation and epithelial cell apoptosis.