Semaporin3A inhibitor ameliorates renal fibrosis through the regulation of JNK signaling
Semaporin3A inhibitor ameliorates renal fibrosis through the regulation of JNK signaling
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Semaporin3A 抑制剂通过调节 JNK 信号传导改善肾纤维化
DOI：
10.1152/ajprenal.00234.2021
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发表时间：
2021
影响因子：
4.2
通讯作者：
Jun Wada
中科院分区：
文献类型：
--
作者：
Yizhen Sang;Kenji Tsuji;Kazuhiko Fukushima;Kensaku Takahashi;Shinji Kitamura;Jun Wada
肾纤维化是进行性肾脏疾病的常见病理途径。在本研究中，我们使用单侧输尿管梗阻 (UUO) 小鼠模型分析了 semaphorin 3 A (SEMA3A) 对肾纤维化的作用以及 SEMA3A 抑制剂 (SEMA3A-I) 的作用。在 UUO 肾中，近端肾小管中的 SEMA3A 以及成纤维细胞和肾小管细胞中的 Neuropilin-1（SEMA3A 的受体）的表达增加。 UUO 肾脏中肌成纤维细胞标记物生腱蛋白-C 的表达和纤维连接以及肾纤维化均增加，所有这些均被 SEMA3A-I 改善。此外，UUO手术后，被称为SEMA3A信号传导靶点的JNK信号通路在近端肾小管细胞和成纤维细胞中被激活，而SEMA3A-I显着减弱了该激活。在体外，用 SEMA3A 以及转化生长因子-β1 (TGF-β1) 处理人近端肾小管细胞，导致上皮细胞特征丧失，而 SEMA3A-I 显着改善了这种转变。 JNK 抑制剂 SP600125 部分逆转 SEMA3A 和 TGF-β1 诱导的细胞转化，表明 JNK 信号传导参与 SEMA3A 诱导的肾纤维化。此外，在成纤维细胞中用SEMA3A处理可激活腱蛋白-C、I型胶原蛋白和纤维连接的表达，表明SEMA3A可能通过激活成纤维细胞来加速肾纤维化。对人体数据的分析显示尿液 SEMA3A 与尿液 N-乙酰基-β-d-氨基葡萄糖苷酶之间呈正相关，表明 SEMA3A 与肾小管损伤之间存在关联。总之，SEMA3A信号通过JNK信号通路参与肾纤维化，SEMA3A-I可能是预防肾纤维化的治疗选择。新与值得注意肾纤维化是肾脏疾病进展的常见病理途径。这项研究使用单侧输尿管梗阻 (UUO) 小鼠模型，表明 UUO 手术后肾小管细胞和成纤维细胞中的 semaphorin3A (SEMA3A) 信号传导增加，SEMA3A 抑制剂通过调节 JNK 信号传导改善 UUO 诱导的肾纤维化。该研究提出了SEMA3A抑制剂治疗肾纤维化的潜在治疗选择。
Renal fibrosis is the common pathological pathway in progressive renal diseases. In the present study, we analyzed the roles of semaphorin 3 A (SEMA3A) on renal fibrosis and the effect of SEMA3A inhibitor (SEMA3A-I) using a unilateral ureteral obstruction (UUO) mouse model. Expression of SEMA3A in the proximal tubulus and neuropilin-1, a recepor of SEMA3A, in fibloblast and tubular cells were increased in UUO kidneys. The expression of myofibroblast marker tenascin-C and fibronection as well as renal fibrosis were increased in UUO kidneys, all of which were ameliorated by SEMA3A-I. In addition, the JNK signaling pathway, known as the target of SEMA3A signaling, was activated in proximal tubular cells and fibroblast cells after UUO surgery, and SEMA3A-I significantly attenuated the activation. In vitro, treatments with SEMA3A as well as transforming growth factor-β1 (TGF-β1) in human proximal tubular cells lost epithelial cell characteristics, and SEMA3A-I significantly ameliorated this transformation. The JNK inhibitor SP600125 partially reversed SEMA3A and TGF-β1-induced cell transformation, indicating that JNK signaling is involved in SEMA3A-induced renal fibrosis. In addition, treatment with SEMA3A in fibroblast cells activated expression of tenascin-C, collagen type I, and fibronection, indicating that SEMA3A may accelerate renal fibrosis through the activation of fibroblast cells. Analysis of human data revealed the positive correlation between urinary SEMA3A and urinaryN-acetyl-β-d-glucosaminidase, indicating the association between SEMA3A and tubular injury. In conclusion, SEMA3A signaling is involved in renal fibrosis through the JNK signaling pathway and SEMA3A-I might be a therapeutic option for protecting from renal fibrosis.NEW & NOTEWORTHYRenal fibrosis is the common pathological pathway in the progression of renal diseases. This study, using a unilateral ureteral obstruction (UUO) mouse model, indicated increased semaphorin3A (SEMA3A) signaling in renal tubular cells as well as fibroblast cells under UUO surgery, and SEMA3A inhibitor ameliorated UUO-induced renal fibrosis through the regulation of JNK signaling. The study proposes the potential therapeutic option of SEMA3A inhibitor to treat renal fibrosis.