CLC number:
On-line Access: 2024-08-27
Received: 2023-10-17
Revision Accepted: 2024-05-08
Crosschecked: 2024-04-07
Cited: 0
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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.
[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.
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