Full Text:   <409>

Summary:  <252>

CLC number: 

On-line Access: 2024-08-27

Received: 2023-10-17

Revision Accepted: 2024-05-08

Crosschecked: 2024-04-07

Cited: 0

Clicked: 786

Citations:  Bibtex RefMan EndNote GB/T7714

 ORCID:

Caiyun FU

https://orcid.org/0000-0003-4090-885X

-   Go to

Article info.
Open peer comments

Journal of Zhejiang University SCIENCE B 2024 Vol.25 No.4 P.341-353

http://doi.org/10.1631/jzus.B2300033


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


Author(s):  Zhibin YAN, Ying SHI, Runling YANG, Jijun XUE, Caiyun FU

Affiliation(s):  Zhejiang Provincial Key Laboratory of Silkworm Bioreactor and Biomedicine, College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou 310018, China; more

Corresponding email(s):   fucy03@zstu.edu.cn

Key Words:  ELA13, Kidney fibrosis, Inflammation, Smad, Extracellular signal-regulated kinase (ERK)


Zhibin YAN, Ying SHI, Runling YANG, Jijun XUE, Caiyun FU. ELABELA-derived peptide ELA13 attenuates kidney fibrosis by inhibiting the Smad and ERK signaling pathways[J]. Journal of Zhejiang University Science B, 2024, 25(4): 341-353.

@article{title="ELABELA-derived peptide ELA13 attenuates kidney fibrosis by inhibiting the Smad and ERK signaling pathways",
author="Zhibin YAN, Ying SHI, Runling YANG, Jijun XUE, Caiyun FU",
journal="Journal of Zhejiang University Science B",
volume="25",
number="4",
pages="341-353",
year="2024",
publisher="Zhejiang University Press & Springer",
doi="10.1631/jzus.B2300033"
}

%0 Journal Article
%T ELABELA-derived peptide ELA13 attenuates kidney fibrosis by inhibiting the Smad and ERK signaling pathways
%A Zhibin YAN
%A Ying SHI
%A Runling YANG
%A Jijun XUE
%A Caiyun FU
%J Journal of Zhejiang University SCIENCE B
%V 25
%N 4
%P 341-353
%@ 1673-1581
%D 2024
%I Zhejiang University Press & Springer
%DOI 10.1631/jzus.B2300033

TY - JOUR
T1 - ELABELA-derived peptide ELA13 attenuates kidney fibrosis by inhibiting the Smad and ERK signaling pathways
A1 - Zhibin YAN
A1 - Ying SHI
A1 - Runling YANG
A1 - Jijun XUE
A1 - Caiyun FU
J0 - Journal of Zhejiang University Science B
VL - 25
IS - 4
SP - 341
EP - 353
%@ 1673-1581
Y1 - 2024
PB - Zhejiang University Press & Springer
ER -
DOI - 10.1631/jzus.B2300033


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.

ELABELA衍生肽ELA13通过抑制Smad和ERK信号通路减轻肾纤维化

闫志斌1,史影2,杨润玲3,薛吉军2,付彩云1,3
1浙江理工大学生命科学与医药学院,浙江省家蚕生物反应器和生物医药重点实验室,中国杭州市,310018
2兰州大学化学化工学院,功能有机分子化学国家重点实验室,中国兰州市,730000
3兰州大学甘肃省新药临床前研究重点实验室,中国医学科学院多肽研究创新单元(2019RU066),中国兰州市,730000
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。

关键词:ELA13;肾纤维化;炎症反应;Smad;细胞外调节蛋白激酶(ERK)

Darkslateblue:Affiliate; Royal Blue:Author; Turquoise:Article

Reference

[1]AkterT, RahmanMA, MoniA, et al., 2021. Prospects for protective potential of Moringa oleifera against kidney diseases. Plants, 10(12):2818.

[2]BoucherJ, MasriB, DaviaudD, et al., 2005. Apelin, a newly identified adipokine up-regulated by insulin and obesity. Endocrinology, 146(4):1764-1771.

[3]ChenH, WangL, WangWJ, et al., 2017. ELABELA and an ELABELA fragment protect against AKI. J Am Soc Nephrol, 28(9):2694-2707.

[4]ChenW, YuanH, CaoWM, et al., 2019. Blocking interleukin-6 trans-signaling protects against renal fibrosis by suppressing STAT3 activation. Theranostics, 9(14):3980-3991.

[5]ChengJF, EncarnacionMMD, WarnerGM, et al., 2005. TGF-β1 stimulates monocyte chemoattractant protein-1 expression in mesangial cells through a phosphodiesterase isoenzyme 4-dependent process. Am J Physiol Cell Physiol, 289(4):C959-C970.

[6]CreweC, AnYA, SchererPE, 2017. The ominous triad of adipose tissue dysfunction: inflammation, fibrosis, and impaired angiogenesis. J Clin Invest, 127(1):74-82.

[7]DengC, ChenHD, YangN, et al., 2015. Apela regulates fluid homeostasis by binding to the APJ receptor to activate Gi signaling. J Biol Chem, 290(30):18261-18268.

[8]DingY, KimSL, LeeSY, et al., 2014. Autophagy regulates TGF‍-‍β expression and suppresses kidney fibrosis induced by unilateral ureteral obstruction. J Am Soc Nephrol, 25(12):2835-2846.

[9]el AghaE, KramannR, SchneiderRK, et al., 2017. Mesenchymal stem cells in fibrotic disease. Cell Stem Cell, 21(2):166-177.

[10]El-GhoulB, ElieC, SqalliT, et al., 2009. Nonprogressive kidney dysfunction and outcomes in older adults with chronic kidney disease. J Am Geriatr Soc, 57(12):2217-2223.

[11]GengXQ, MaA, HeJZ, et al., 2020. Ganoderic acid hinders renal fibrosis via suppressing the TGF-‍β/Smad and MAPK signaling pathways. Acta Pharmacol Sin, 41(5):670-677.

[12]GilmoreTD, 2006. Introduction to NF-κB: players, pathways, perspectives. Oncogene, 25(51):6680-6684.

[13]GrandeMT, Sánchez-LaordenB, López-BlauC, et al., 2015. Snail1-induced partial epithelial-to-mesenchymal transition drives renal fibrosis in mice and can be targeted to reverse established disease. Nat Med, 21(9):989-997.

[14]HarrisRC, NeilsonEG, 2006. Toward a unified theory of renal progression. Annu Rev Med, 57(1):365-380.

[15]HartsoughMT, MulderKM, 1995. Transforming growth factor β activation of p44mapk in proliferating cultures of epithelial cells. J Biol Chem, 270(13):7117-7124.

[16]HuangXM, JiaZQ, LiXY, et al., 2023. Asiaticoside hampers epithelial‍‒‍mesenchymal transition by promoting PPARG expression and suppressing P2RX7-mediated TGF‍-‍β/Smad signaling in triple-negative breast cancer. Phytother Res, 37(5):1771-1786.

[17]JiXL, WangHL, WuZJ, et al., 2018. Specific Inhibitor of Smad3 (SIS3) attenuates fibrosis, apoptosis, and inflammation in unilateral ureteral obstruction kidneys by inhibition of transforming growth factor β (TGF-‍β)/Smad3 signaling. Med Sci Monit, 24:1633-1641.

[18]JiangS, LiT, YangZ, et al., 2017. AMPK orchestrates an elaborate cascade protecting tissue from fibrosis and aging. Ageing Res Rev, 38:18-27.

[19]KanasakiK, TaduriG, KoyaD, 2013. Diabetic nephropathy: the role of inflammation in fibroblast activation and kidney fibrosis. Front Endocrinol (Lausanne), 4:7.

[20]KandaH, HirasakiY, IidaT, et al., 2017. Perioperative management of patients with end-stage renal disease. J Cardiothorac Vasc Anesth, 31(6):2251-2267.

[21]KorpalM, KangY, 2010. Targeting the transforming growth factor-‍β signalling pathway in metastatic cancer. Eur J Cancer, 46(7):1232-1240.

[22]KovacsRJ, MaldonadoG, AzaroA, et al., 2015. Cardiac Safety of TGF‍-‍β receptor I kinase inhibitor LY2157299 monohydrate in cancer patients in a first-in-human dose study. Cardiovasc Toxicol, 15(4):309-323.

[23]LanHY, 2011. Diverse roles of TGF-β/Smads in renal fibrosis and inflammation. Int J Biol Sci, 7(7):1056-1067.

[24]LeeDK, ChengR, NguyenT, et al., 2000. Characterization of apelin, the ligand for the APJ receptor. J Neurochem, 74(1):34-41.

[25]LiZ, ZhouLL, WangYP, et al., 2017. (Pro)renin receptor is an amplifier of Wnt/β-catenin signaling in kidney injury and fibrosis. J Am Soc Nephrol, 28(8):2393-2408.

[26]López-HernándezFJ, López-NovoaJM, 2012. Role of TGF-‍β in chronic kidney disease: an integration of tubular, glomerular and vascular effects. Cell Tissue Res, 347(1):141-154.

[27]LuJH, ZhongYZ, LinZC, et al., 2017. Baicalin alleviates radiation-induced epithelial-mesenchymal transition of primary type II alveolar epithelial cells via TGF-‍β and ERK/GSK3β signaling pathways. Biomed Pharmacother, 95:1219-1224.

[28]MaleszewskaM, MoonenJRAJ, HuijkmanN, et al., 2013. IL-1β and TGFβ2 synergistically induce endothelial to mesenchymal transition in an NFκB-dependent manner. Immunobiology, 218(4):443-454.

[29]MaramponF, BossiG, CiccarelliC, et al., 2009. MEK/ERK inhibitor U0126 affects in vitro and in vivo growth of embryonal rhabdomyosarcoma. Mol Cancer Ther, 8(3):543-551.

[30]MengJ, LiLM, ZhaoY, et al., 2016. MicroRNA-196a/b mitigate renal fibrosis by targeting TGF‍-‍β receptor 2. J Am Soc Nephrol, 27(10):3006-3021.

[31]MengXM, Nikolic-PatersonDJ, LanHY, 2014. Inflammatory processes in renal fibrosis. Nat Rev Nephrol, 10(9):493-503.

[32]MengXM, TangPMK, LiJ, et al., 2015. TGF-β/Smad signaling in renal fibrosis. Front Physiol, 6:82.

[33]NoronhaIL, FujiharaCK, ZatzR, 2002. The inflammatory component in progressive renal disease—are interventions possible? Nephrol Dial Transplant, 17(3):363-368.

[34]NutterFH, HaylorJL, KhwajaA, 2015. Inhibiting ERK activation with CI-1040 leads to compensatory upregulation of alternate MAPKs and plasminogen activator inhibitor-1 following subtotal nephrectomy with no impact on kidney fibrosis. PLoS ONE, 10(9):e0137321.

[35]O'DowdBF, HeiberM, ChanA, et al., 1993. A human gene that shows identity with the gene encoding the angiotensin receptor is located on chromosome 11. Gene, 136(1-2):355-360.

[36]RahmanMH, BiswasP, DeyD, et al., 2022. An in-silico identification of potential flavonoids against kidney fibrosis targeting TGFβR-1. Life, 12(11):1764.

[37]RahmanMA, AkterS, DoroteaD, et al., 2022. Renoprotective potentials of small molecule natural products targeting mitochondrial dysfunction. Front Pharmacol, 13:925993.

[38]Reichman-FriedM, RazE, 2014. Small proteins, big roles: the signaling protein Apela extends the complexity of developmental pathways in the early zebrafish embryo. Bioessays, 36(8):741-745.

[39]RomagnaniP, KalluriR, 2009. Possible mechanisms of kidney repair. Fibrogenesis Tissue Repair, 2:3.

[40]SchinnerE, WetzlV, SchrammA, et al., 2017. Inhibition of the TGFβ signalling pathway by cGMP and cGMP-dependent kinase I in renal fibrosis. FEBS Open Bio, 7(4):550-561.

[41]SchreiberCA, HolditchS, GenerousA, et al., 2016. Sustained ELABELA gene therapy in high-salt diet-induced hypertensive rats. Curr Gene Therapy, 16(5):349-360.

[42]SesekeF, ThelenP, RingertRH, 2004. Characterization of an animal model of spontaneous congenital unilateral obstructive uropathy by cDNA microarray analysis. Eur Urol, 45(3):374-381.

[43]ShenWC, LiangCJ, HuangTM, et al., 2016. Indoxyl sulfate enhances IL-1β‍-induced E-selectin expression in endothelial cells in acute kidney injury by the ROS/MAPKs/NFκB/AP-1 pathway. Arch Toxicol, 90(11):2779-2792.

[44]SunSR, NingXX, ZhaiY, et al., 2014. Egr-1 mediates chronic hypoxia-induced renal interstitial fibrosis via the PKC/ERK pathway. Am J Nephrol, 39(5):436-448.

[45]TampeD, ZeisbergM, 2014. Potential approaches to reverse or repair renal fibrosis. Nat Rev Nephrol, 10(4):226-237.

[46]TanakaS, TanakaT, NangakuM, 2015. Hypoxia and dysregulated angiogenesis in kidney disease. Kidney Dis, 1(1):80-89.

[47]WadaT, FuruichiK, SakaiN, et al., 2004. Gene therapy via blockade of monocyte chemoattractant protein-1 for renal fibrosis. J Am Soc Nephrol, 15(4):940-948.

[48]WangGY, AniniY, WeiW, et al., 2004. Apelin, a new enteric peptide: localization in the gastrointestinal tract, ontogeny, and stimulation of gastric cell proliferation and of cholecystokinin secretion. Endocrinology, 145(3):1342-1348.

[49]WangLY, DiaoZL, ZhangDL, et al., 2014. The regulatory peptide apelin: a novel inhibitor of renal interstitial fibrosis. Amino Acids, 46(12):2693-2704.

[50]WangSN, LaPageJ, HirschbergR, 2000. Role of glomerular ultrafiltration of growth factors in progressive interstitial fibrosis in diabetic nephropathy. Kidney Int, 57(3):‍1002-1014.

[51]WangZ, YuDZ, WangMQ, et al., 2015. Elabela-apelin receptor signaling pathway is functional in mammalian systems. Sci Rep, 5:8170.

[52]WojciechowskiMC, ShuDY, LovicuFJ, 2018. ERK1/2-dependent gene expression contributing to TGFβ‍-induced lens EMT. Curr Eye Res, 43(8):986-997.

[53]XuT, WangNS, FuLL, et al., 2012. Celecoxib inhibits growth of human autosomal dominant polycystic kidney cyst-lining epithelial cells through the VEGF/Raf/MAPK/ERK signaling pathway. Mol Biol Rep, 39(7):7743-7753.

[54]XueHY, YuanL, CaoYJ, et al., 2016. Resveratrol amelior

[55]ates renal injury in spontaneously hypertensive rats by inhibiting renal micro-inflammation. Biosci Rep, 36(3):e00339.

[56]YanZB, ChengXR, WangT, et al., 2022. Therapeutic potential for targeting Annexin A1 in fibrotic diseases. Genes Dis, 9(6):1493-1505.

[57]YangL, GuoJ, YuN, et al., 2020. Tocilizumab mimotope alleviates kidney injury and fibrosis by inhibiting IL-6 signaling and ferroptosis in UUO model. Life Sci, 261:118487.

[58]ZeisbergM, NeilsonEG, 2010. Mechanisms of tubulointerstitial fibrosis. J Am Soc Nephrol, 21(11):1819-1834.

[59]ZhangDS, SunL, XianW, et al., 2010. Low-dose paclitaxel ameliorates renal fibrosis in rat UUO model by inhibition of TGF-β/Smad activity. Lab Invest, 90(3):436-447.

[60]ZhangYH, WangSY, LiuSM, et al., 2015. Role of Smad signaling in kidney disease. Int Urol Nephrol, 47(12):‍1965-1975.

[61]ZhangYX, WangYW, LuoMY, et al., 2019. Elabela protects against podocyte injury in mice with streptozocin-induced diabetes by associating with the PI3K/Akt/mTOR pathway. Peptides, 114:29-37.

[62]ZhuangZH, TongMK, ClarkeR, et al., 2022. Probability of chronic kidney disease and associated risk factors in Chinese adults: a cross-sectional study of 9 million Chinese adults in the Meinian Onehealth screening survey. Clin Kidney J, 15(12):2228-2236.

Open peer comments: Debate/Discuss/Question/Opinion

<1>

Please provide your name, email address and a comment





Journal of Zhejiang University-SCIENCE, 38 Zheda Road, Hangzhou 310027, China
Tel: +86-571-87952783; E-mail: cjzhang@zju.edu.cn
Copyright © 2000 - 2024 Journal of Zhejiang University-SCIENCE