Semaphorin3A-Inhibitor Ameliorates Doxorubicin-Induced Podocyte Injury
Semaphorin3A-Inhibitor Ameliorates Doxorubicin-Induced Podocyte Injury
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DOI：
10.3390/ijms21114099
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发表时间：
2020-06
影响因子：
5.6
通讯作者：
Yizhen Sang;Kenji Tsuji;Akiko Inoue-Torii;Kazuhiko Fukushima;S. Kitamura;J. Wada
中科院分区：
文献类型：
--
作者：
Yizhen Sang;Kenji Tsuji;Akiko Inoue-Torii;Kazuhiko Fukushima;S. Kitamura;J. Wada
足细胞损伤是肾脏疾病进展的独立危险因素。脑信号蛋白3A（Semaphorin 3A，SEMA 3A）表达于成年哺乳动物肾脏的足细胞和肾小管细胞，具有多种生物学功能，与肾脏疾病有关。在这里，我们使用阿霉素（Dox）诱导的小鼠模型研究了SEMA 3A信号传导对足细胞损伤的病理作用，并检查了SEMA 3A抑制剂（SEMA 3A-I）的治疗效果。我们证明Dox引起大量蛋白尿和足细胞凋亡以及足细胞中SEMA 3A表达的增加，所有这些都通过SEMA 3A-I治疗得到改善。此外，c-Jun N-末端激酶（JNK），被称为SEMA 3A信号传导的下游，在Dox注射的小鼠足细胞中被激活，而SEMA 3A-I治疗部分阻断了激活。在体外，SEMA 3A-I保护Dox诱导的足细胞凋亡，重组SEMA 3A通过激活JNK信号通路引起足细胞凋亡。JNK抑制剂SP 600125可减弱SEMA 3A诱导的足细胞凋亡，表明JNK通路可能参与SEMA 3A诱导的足细胞凋亡。此外，对人类数据的分析揭示了尿SEMA 3A和蛋白质水平之间的正相关性，表明SEMA 3A与足细胞损伤相关。因此，SEMA 3A在足细胞损伤中具有重要作用，有望成为足细胞损伤保护的治疗靶点。
Podocyte injury is an independent risk factor for the progression of renal diseases. Semaphorin3A (SEMA3A), expressed in podocytes and tubular cells in the mammalian adult kidneys, has been reported to regulate diverse biological functions and be associated with renal diseases. Here, we investigated pathological roles of SEMA3A signaling on podocyte injury using a doxorubicin (Dox)-induced mouse model and examined the therapeutic effect of SEMA3A-inhibitor (SEMA3A-I). We demonstrated that Dox caused massive albuminuria and podocyte apoptosis as well as an increase of SEMA3A expression in podocytes, all of which were ameliorated with SEMA3A-I treatment. In addition, c-Jun N-terminal kinase (JNK), known as a downstream of SEMA3A signaling, was activated in Dox-injected mouse podocytes while SEMA3A-I treatment partially blocked the activation. In vitro, SEMA3A-I protected against Dox-induced podocyte apoptosis and recombinant SEMA3A caused podocyte apoptosis with activation of JNK signaling. JNK inhibitor, SP600125, attenuated SEMA3A-induced podocyte apoptosis, indicating that the JNK pathway would be involved in SEMA3A-induced podocyte apoptosis. Furthermore, the analysis of human data revealed a positive correlation between levels of urinary SEMA3A and protein, suggesting that SEMA3A is associated with podocyte injury. In conclusion, SEMA3A has essential roles in podocyte injury and it would be the therapeutic target for protecting from podocyte injury.