ELABELA-derived peptide ELA13 attenuates kidney fibrosis by inhibiting the Smad and ERK signaling pathways

Zhibin YAN; Ying SHI; Runling YANG; Jijun XUE; Caiyun FU

doi:10.1631/jzus.B2300033

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ELABELA-derived peptide ELA13 attenuates kidney fibrosis by inhibiting the Smad and ERK signaling pathways

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Research Article | Updated：2024-04-07

ELABELA-derived peptide ELA13 attenuates kidney fibrosis by inhibiting the Smad and ERK signaling pathways
ELABELA-derived peptide ELA13 attenuates kidney fibrosis by inhibiting the Smad and ERK signaling pathways
ELABELA衍生肽ELA13通过抑制Smad和ERK信号通路减轻肾纤维化
Journal of Zhejiang University-SCIENCE B (Biomedicine & Biotechnology) Vol. 25, Issue 4, Pages: 341-353(2024)
Affiliations：

1.Zhejiang Provincial Key Laboratory of Silkworm Bioreactor and Biomedicine, College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou 310018, China
2.State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou 730000, China
3.Key Laboratory of Preclinical Study for New Drugs of Gansu Province, School of Basic Medical Sciences & Research Unit of Peptide Science, Chinese Academy of Medical Sciences, 2019RU066, Lanzhou University, Lanzhou 730000, China
Funds：
DOI：10.1631/jzus.B2300033
CLC：
CSTR：
Published： 15 April 2024 ，

Received： 11 January 2023 ，

Revised： 13 April 2023 ，

闫志斌,史影,杨润玲等.ELABELA衍生肽ELA13通过抑制Smad和ERK信号通路减轻肾纤维化[J].浙江大学学报（英文版）（B辑：生物医学和生物技术）,2024,25(04):341-353.

Zhibin YAN, Ying SHI, Runling YANG, et al. ELABELA-derived peptide ELA13 attenuates kidney fibrosis by inhibiting the Smad and ERK signaling pathways. [J]. Journal of Zhejiang University-SCIENCE B (Biomedicine & Biotechnology) 25(4):341-353(2024)
闫志斌,史影,杨润玲等.ELABELA衍生肽ELA13通过抑制Smad和ERK信号通路减轻肾纤维化[J].浙江大学学报（英文版）（B辑：生物医学和生物技术）,2024,25(04):341-353. DOI： 10.1631/jzus.B2300033.

Zhibin YAN, Ying SHI, Runling YANG, et al. ELABELA-derived peptide ELA13 attenuates kidney fibrosis by inhibiting the Smad and ERK signaling pathways. [J]. Journal of Zhejiang University-SCIENCE B (Biomedicine & Biotechnology) 25(4):341-353(2024) DOI： 10.1631/jzus.B2300033.

摘要

肾脏纤维化是各种慢性肾脏疾病发展为终末期肾病的关键过程。目前尚无针对肾纤维化的特异性治疗方法。ELA13（氨基酸序列：RRCMPLHSRVPFP）是ELABELA在所有脊椎动物中的保守片段，目前对其生物学活性的研究却很少。本研究评估了ELA13对转化生长因子β1（TGF-β1）处理的NRK-52E细胞和单侧输尿管闭塞（UUO）小鼠的作用效果。首先，体外实验表明在TGF-β1诱导的NRK-52E细胞中，ELA13可以降低纤维化标志物I型胶原（Collagen I）、纤连蛋白（fibronectin）和α-平滑肌肌动蛋白（α-SMA）的表达水平。随后，在UUO诱导的小鼠肾纤维化模型中，我们发现ELA13可以通过降低血清中肌酐和尿素氮的含量来改善肾功能，并通过Masson染色、免疫组织化学、实时定量聚合酶链式反应（RT-PCR）和蛋白质印迹（western blot）的结果证实纤维化标志物和炎症标志物的表达降低了。进一步机制研究发现，ELA13处理可抑制Smad和细胞外调节蛋白激酶（ERK）信号通路。综上所述，ELA13通过抑制Smad和ERK信号通路发挥抗肾纤维化的作用，有望成为抗肾纤维化治疗的候选分子。

Abstract

Kidney fibrosis is an inevitable result of various chronic kidney diseases (CKDs) and significantly contributes to end-stage renal failure. Currently

there is no specific treatment available for renal fibrosis. ELA13 (amino acid sequence: RRCMPLHSRVPFP) is a conserved region of ELABELA in all vertebrates; however

its biological activity has been very little studied. In the present study

we evaluated the therapeutic effect of ELA13 on transforming growth factor-β1 (TGF-β1)-treated NRK-52E cells and unilateral ureteral occlusion (UUO) mice. Our results demonstrated that ELA13 could improve renal function by reducing creatinine and urea nitrogen content in serum

and reduce the expression of fibrosis biomarkers confirmed by Masson staining

immunohistochemistry

real-time polymerase chain reaction (RT-PCR)

and western blot. Inflammation biomarkers were increased after UUO and decreased by administration of ELA13. Furthermore

we found that the levels of essential molecules in the mothers against decapentaplegic (Smad) and extracellular signal-regulated kinase (ERK) pathways were reduced by ELA13 treatment in vivo and in vitro. In conclusion

ELA13 protected against kidney fibrosis through inhibiting the Smad and ERK signaling pathways and could thus be a promising candidate for anti-renal fibrosis treatment.

关键词

ELA13肾纤维化炎症反应Smad细胞外调节蛋白激酶（ERK）

Keywords

ELA13Kidney fibrosisInflammationSmadExtracellular signal-regulated kinase (ERK)

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