Department of Nephrology, Rheumatology, Endocrinology, and Metabolism, Okayama University Academic Field of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan.
Am J Physiol Renal Physiol. 2021 Dec 1;321(6):F740-F756. doi: 10.1152/ajprenal.00234.2021. Epub 2021 Nov 8.
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 urinary -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. Renal 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.
肾纤维化是进行性肾脏疾病的共同病理途径。在本研究中，我们使用单侧输尿管梗阻 (UUO) 小鼠模型分析了信号素 3A (SEMA3A) 在肾纤维化中的作用和 SEMA3A 抑制剂 (SEMA3A-I) 的作用。在 UUO 肾脏中，近端肾小管中 SEMA3A 的表达以及成纤维细胞和管状细胞中 SEMA3A 的受体神经纤毛蛋白-1 (neuropilin-1) 的表达增加。UUO 肾脏中肌成纤维细胞标志物腱糖蛋白 C 和纤维连接蛋白以及肾纤维化的表达增加，而 SEMA3A-I 可改善这些变化。此外，已知 JNK 信号通路是 SEMA3A 信号的靶标，在 UUO 手术后近端肾小管细胞和成纤维细胞中被激活，而 SEMA3A-I 可显著抑制其激活。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会失去上皮细胞特征，而 SEMA3A-I 可显著改善这种转化。JNK 抑制剂 SP600125 部分逆转了 SEMA3A 和 TGF-β1 诱导的细胞转化，表明 JNK 信号参与了 SEMA3A 诱导的肾纤维化。此外，用 SEMA3A 处理成纤维细胞可激活腱糖蛋白 C、胶原 I 和纤维连接蛋白的表达，表明 SEMA3A 可能通过激活成纤维细胞加速肾纤维化。对人类数据的分析表明，尿 SEMA3A 与尿乙酰-β-D-氨基葡萄糖苷酶呈正相关，表明 SEMA3A 与肾小管损伤有关。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一种治疗选择。
