JPH203 alleviates renal fibrosis via inhibition of serine-related mTORC1 pathway in TGF-β1-induced fibroblasts and UUO mice

IF 3.5 3区 生物学 Q3 CELL BIOLOGY
Changwan Cui , Mengqi Hong , Hainan Zhao , Lei Wang , Ying Yang , Jingyu Wang , Li Sun
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引用次数: 0

Abstract

Renal fibrosis is the common pathological outcome of chronic kidney disease (CKD) progressing into end-stage renal disease. The excessive proliferation of fibroblasts plays an important role in the CKD progression. Nutrients such as amino acids and their transportation are essential for cell proliferation. In this study, TGF-β1-induced fibroblasts and UUO mouse models were used. The target gene solute carrier family 7 member 5 (SLC7A5) was screened to be highly expressed and localized in the renal fibroblasts of CKD mice. In vivo experiments showed that SLC7A5 promoted the activation of mammalian target of rapamycin complex 1 (mTORC1) signaling pathway, enhanced serine synthesis and maintained oxidative stress balance in fibroblasts. SLC7A5 increased the expression of transcription factor activating transcription factor 4 (ATF4), promoted the transcription of serine de-novo synthesis enzyme PHGDH, and increased the synthesis of glutathione, a byproduct of serine synthesis pathway. JPH203, a specific inhibitor of SLC7A5, effectively reversed the above phenomena, inhibited mTORC1 signaling activation, and reduced the proliferation of fibroblasts. The efficacy of JPH203 was further verified by in vivo experiments. JPH203 had a similar effect to the inhibitory adenovirus AV-shSLC7A5 in the UUO mouse model. Compared with the UUO group, the activation of mTORC1 pathway in the JPH203 treatment group was inhibited, and the expressions of α-SMA and vimentin in fibroblasts were decreased. The fibrotic state of renal tissues was effectively relieved. In addition, the levels of serum creatinine, blood urea nitrogen and pelvic urinary protein were significantly decreased compared with the UUO group. In conclusion, our study demonstrated that JPH203 can alleviate renal fibrosis via inhibition of serine-related mTORC1 pathway in fibroblasts in UUO mice. These results may provide a theoretical foundation for the pathogenesis of renal fibrosis and a novel therapeutic strategy for CKD.
在TGF-β1诱导的成纤维细胞和UUO小鼠中,JPH203通过抑制丝氨酸相关的mTORC1通路减轻肾纤维化。
肾纤维化是慢性肾脏疾病(CKD)进展为终末期肾脏疾病的常见病理结果。成纤维细胞的过度增殖在CKD的进展中起重要作用。氨基酸等营养物质及其运输对细胞增殖至关重要。本研究采用TGF-β1诱导成纤维细胞和UUO小鼠模型。筛选到靶基因溶质载体家族7成员5 (SLC7A5)在CKD小鼠肾成纤维细胞中高表达和定位。体内实验表明,SLC7A5促进了哺乳动物雷帕霉素靶蛋白复合物1 (mTORC1)信号通路的激活,增强了丝氨酸合成,维持了成纤维细胞的氧化应激平衡。SLC7A5增加转录因子激活转录因子4 (ATF4)的表达,促进丝氨酸去新生合成酶PHGDH的转录,增加丝氨酸合成途径副产物谷胱甘肽的合成。SLC7A5特异性抑制剂JPH203有效逆转上述现象,抑制mTORC1信号的激活,降低成纤维细胞的增殖。通过体内实验进一步验证了JPH203的有效性。JPH203在UUO小鼠模型中具有与抑制性腺病毒AV-shSLC7A5相似的作用。与UUO组相比,JPH203治疗组mTORC1通路激活被抑制,成纤维细胞α-SMA和vimentin表达降低。肾脏组织的纤维化状态得到有效缓解。血清肌酐、血尿素氮、盆腔尿蛋白水平均较UUO组显著降低。综上所述,我们的研究表明JPH203可以通过抑制UUO小鼠成纤维细胞中丝氨酸相关的mTORC1通路来减轻肾纤维化。这些结果可能为肾脏纤维化的发病机制和CKD的新治疗策略提供理论基础。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Experimental cell research
Experimental cell research 医学-细胞生物学
CiteScore
7.20
自引率
0.00%
发文量
295
审稿时长
30 days
期刊介绍: Our scope includes but is not limited to areas such as: Chromosome biology; Chromatin and epigenetics; DNA repair; Gene regulation; Nuclear import-export; RNA processing; Non-coding RNAs; Organelle biology; The cytoskeleton; Intracellular trafficking; Cell-cell and cell-matrix interactions; Cell motility and migration; Cell proliferation; Cellular differentiation; Signal transduction; Programmed cell death.
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