Inhibition of renal fibrosis with a human CXCL9-derived glycosaminoglycan-binding peptide

IF 4.6 2区医学 Q2 IMMUNOLOGY

Clinical & Translational Immunology Pub Date : 2022-02-02 DOI:10.1002/cti2.1370

Fariba Poosti, Mohammad Ayodhia Soebadi, Helena Crijns, Alexandra De Zutter, Mieke Metzemaekers, Nele Berghmans, Vincent Vanheule, Maarten Albersen, Ghislain Opdenakker, Jo Van Damme, Ben Sprangers, Paul Proost, Sofie Struyf

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引用次数: 2

Abstract

Objectives

Renal fibrosis accompanies all chronic kidney disorders, ultimately leading to end-stage kidney disease and the need for dialysis or even renal replacement. As such, renal fibrosis poses a major threat to global health and the search for effective therapeutic strategies to prevent or treat fibrosis is highly needed. We evaluated the applicability of a highly positively charged human peptide derived from the COOH-terminal domain of the chemokine CXCL9, namely CXCL9(74–103), for therapeutic intervention. Because of its high density of net positive charges at physiological pH, CXCL9(74–103) competes with full-length chemokines for glycosaminoglycan (GAG) binding. Consequently, CXCL9(74–103) prevents recruitment of inflammatory leucocytes to sites of inflammation.

Methods

CXCL9(74–103) was chemically synthesised and tested in vitro for anti-fibrotic properties on human fibroblasts and in vivo in the unilateral ureteral obstruction (UUO) mouse model.

Results

CXCL9(74–103) significantly reduced the mRNA and/or protein expression of connective tissue growth factor (CTGF), alpha-smooth muscle actin (α-SMA) and collagen III by transforming growth factor (TGF)-β1-stimulated human fibroblasts. In addition, administration of CXCL9(74–103) inhibited fibroblast migration towards platelet-derived growth factor (PDGF), without affecting cell viability. In the UUO model, CXCL9(74–103) treatment significantly decreased renal α-SMA, vimentin, and fibronectin mRNA and protein expression. Compared with vehicle, CXCL9(74–103) attenuated mRNA expression of TGF-β1 and the inflammatory markers/mediators MMP-9, F4/80, CCL2, IL-6 and TNF-α. Finally, CXCL9(74–103) treatment resulted in reduced influx of leucocytes in the UUO model and preserved tubular morphology. The anti-fibrotic and anti-inflammatory effects of CXCL9(74–103) were mediated by competition with chemokines and growth factors for GAG binding.

Conclusions

Our findings provide a scientific rationale for targeting GAG–protein interactions in renal fibrotic disease.

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人cxcl9衍生糖胺聚糖结合肽对肾纤维化的抑制作用

肾纤维化伴随所有慢性肾脏疾病，最终导致终末期肾脏疾病，需要透析甚至肾脏替代。因此，肾纤维化对全球健康构成重大威胁，迫切需要寻找有效的治疗策略来预防或治疗纤维化。我们评估了从趋化因子CXCL9的cooh末端区域衍生的高度带正电的人肽(即CXCL9)在治疗干预中的适用性(74-103)。由于CXCL9(74-103)在生理pH值下具有高密度的净正电荷，因此可以与全长趋化因子竞争糖胺聚糖(GAG)的结合。因此，CXCL9(74-103)阻止炎性白细胞向炎症部位募集。方法化学合成CXCL9(74-103)，体外对人成纤维细胞和单侧输尿管梗阻(UUO)小鼠模型进行抗纤维化实验。结果CXCL9(74-103)通过转化生长因子(TGF)-β1刺激人成纤维细胞，显著降低结缔组织生长因子(CTGF)、α-平滑肌肌动蛋白(α-SMA)和III型胶原mRNA和/或蛋白的表达。此外，CXCL9(74-103)抑制成纤维细胞向血小板衍生生长因子(PDGF)迁移，而不影响细胞活力。在UUO模型中，CXCL9(74-103)处理显著降低肾脏α-SMA、vimentin和纤维连接蛋白mRNA和蛋白的表达。与对照组相比，CXCL9(74-103)可降低TGF-β1 mRNA及炎症标志物/介质MMP-9、F4/80、CCL2、IL-6和TNF-α的表达。最后，CXCL9(74-103)处理导致UUO模型中白细胞内流减少，并保留了小管形态。CXCL9(74-103)的抗纤维化和抗炎作用是通过与趋化因子和生长因子竞争GAG结合介导的。结论我们的研究结果为靶向gag -蛋白在肾纤维化疾病中的相互作用提供了科学依据。

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

Clinical & Translational Immunology Medicine-Immunology and Allergy

CiteScore

12.00

自引率

1.70%

发文量

审稿时长

13 weeks

期刊介绍： Clinical & Translational Immunology is an open access, fully peer-reviewed journal devoted to publishing cutting-edge advances in biomedical research for scientists and physicians. The Journal covers fields including cancer biology, cardiovascular research, gene therapy, immunology, vaccine development and disease pathogenesis and therapy at the earliest phases of investigation.