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中华肾病研究电子杂志 ›› 2025, Vol. 14 ›› Issue (03) : 158 -163. doi: 10.3877/cma.j.issn.2095-3216.2025.03.007

综述

通过干预转化生长因子-β/哺乳动物母体抗十五肢体瘫痪蛋白经典信号通路防治肾脏纤维化的研究进展
刘姗姗1, 赵晓娇1, 乔玉峰1,()   
  1. 1. 030001 太原,山西医科大学附属山西省人民医院肾内科
  • 收稿日期:2024-11-13 出版日期:2025-06-28
  • 通信作者: 乔玉峰
  • 基金资助:
    山西省自然科学基金项目面上项目(201901D111438)

Research progress on preventing and treating renal fibrosis by intervening in classical TGF-β/Smad signaling pathway

Shanshan Liu1, Xiaojiao Zhao1, Yufeng Qiao1,()   

  1. 1. Department of Nephrology,Shanxi Provincial People′s Hospital Affiliated to Shanxi Medical University,Taiyuan 030001,Shanxi Province,China
  • Received:2024-11-13 Published:2025-06-28
  • Corresponding author: Yufeng Qiao
引用本文:

刘姗姗, 赵晓娇, 乔玉峰. 通过干预转化生长因子-β/哺乳动物母体抗十五肢体瘫痪蛋白经典信号通路防治肾脏纤维化的研究进展[J/OL]. 中华肾病研究电子杂志, 2025, 14(03): 158-163.

Shanshan Liu, Xiaojiao Zhao, Yufeng Qiao. Research progress on preventing and treating renal fibrosis by intervening in classical TGF-β/Smad signaling pathway[J/OL]. Chinese Journal of Kidney Disease Investigation(Electronic Edition), 2025, 14(03): 158-163.

肾脏纤维化是慢性肾脏病的终末期表现形式,其发生机制复杂,涉及多种发病机制及信号通路,其中信号通路包括经典转化生长因子-β/哺乳动物母体抗十五肢体瘫痪蛋白通路、非经典转化生长因子-β/哺乳动物母体抗十五肢体瘫痪蛋白通路和无翅/整合基因/β-连环蛋白通路等;发病机制主要包括细胞外基质过度沉积和肌成纤维细胞的转化与激活。 本文从转化生长因子-β/哺乳动物母体抗十五肢体瘫痪蛋白经典信号通路入手,综述了相关的临床试验和临床前研究进展,旨在为防治肾脏纤维化提供新的思路和参考。

Renal fibrosis is the end-stage manifestation of chronic kidney disease, with a complex mechanism involving multiple pathogenic mechanisms and signaling pathways.The signaling pathways include classical transforming growth factor-β (TGF-β)/mammals maternal against decapentaplegic (Smad)pathway, non-classical TGF-β/Smad pathway, and wingless/integrated (Wnt) gene/β-catenin pathway.The pathogenesis mainly includes excessive deposition of extracellular matrix as well as transformation and activation of myofibroblasts.This article started with the classic TGF-β/Smad signaling pathway and reviewed the relevant clinical trials and preclinical research progress, aiming to provide new ideas and references for preventing and treating renal fibrosis.

图1 经典TGF-β/Smad 信号通路[7] 注:从潜伏相关肽(latency-associated peptide,LAP)-潜伏TGF-β结合蛋白(latent TGF-β-binding protein,LTBP)复合物中释放后,具有生物活性的TGF-β1 同源二聚体与TGF-β 受体2(TGF-β receptor 2,TGFR2)结合募集并激活TGFR1,活化的TGFR1 进而使Smad2 和Smad3 发生磷酸化后与Smad4 形成复合物并转位至细胞核内,该复合物中的Smad3 组分可直接结合基因启动子区域诱导促纤维化分子的转录[包括胶原蛋白(collagens)、纤连蛋白(fibronectin)、α-平滑肌肌动蛋白(α-SMA)和组织金属蛋白酶抑制剂(tissue inhibitor of metalloproteinase type,TIMP)等]促进肌成纤维细胞活化及基质沉积,Smad3 还能诱导促纤维化的微小RNA 和长链非编码RNA 转录,同时间接抑制抗纤维化的微小RNAs 转录。 最后,Smad3 可通过影响DNA 和组蛋白的表观遗传修饰来增强促纤维化分子的转录。 Smad7 作为Smad2/3 的负向调节因子,能够抑制纤维化进程;Protease cleavage:蛋白裂解;Epigenetic modifications(DNA methylation and histone marks):表观遗传修饰(DNA 甲基化与组蛋白标记);Profibrotic miRNA and lncRNA:促纤维化的微小RNA 和长链非编码RNA;Antifibrotic miRNA and lncRNA:抗纤维化的微小RNA 和长链非编码RNA;Myofibroblast activation and matrix deposition:肌成纤维细胞活化与基质沉积
[1]
Shen P, Deng X, Li T, et al.Demethylzeylasteral protects against renal interstitial fibrosis by attenuating mitochondrial complex I-mediated oxidative stress [J].J Ethnopharmacol,2024,327:117986.
[2]
Xu H, Wang M, Li Y, et al.Blocking connexin 43 and its promotion of ATP release from renal tubular epithelial cells ameliorates renal fibrosis [J].Cell Death Dis, 2022, 13(5):511.
[3]
Aashaq S,Batool A,Mir SA,et al.TGF-β signaling:a recap of Smad-independent and Smad-dependent pathways [J].J Cell Physiol,2022,237(1):59-85.
[4]
Tzavlaki K, Moustakas A.TGF-β signaling [J].Biomolecules,2020,10(3):487.
[5]
Li J,Zou Y,Kantapan J,et al.TGF-β/Smad signaling in chronic kidney disease: exploring post-translational regulatory perspectives(Review) [J].Mol Med Rep,2024,30(2):143.
[6]
Zhong J, Zou H.BMP signaling in axon regeneration [J].Curr Opin Neurobiol,2014,27:127-134.
[7]
Meng XM, Nikolic-Paterson DJ, Lan HY.TGF-β: the master regulator of fibrosis [J].Nat Rev Nephrol,2016,12(6):325-338.
[8]
Vega G, Alarcón S, San Martín R.The cellular and signalling alterations conducted by TGF-β contributing to renal fibrosis[J].Cytokine,2016,88:115-125.
[9]
Gu YY, Liu XS, Huang XR, et al.TGF-β in renal fibrosis:triumphs and challenges[J].Future Med Chem,2020,12(9):853-866.
[10]
Meng X, Jin J, Lan HY.Driving role of macrophages in transition from acute kidney injury to chronic kidney disease[J].Chin Med J (Engl),2022,135(7):757-766.
[11]
Humphreys BD.Mechanisms of renal fibrosis [J].Annu Rev Physiol,2018,80:309-326.
[12]
Qing Z, Yuan W, Wang J, et al.Verapamil inhibited the development of ureteral stricture by blocking CaMK II-mediated STAT3 and Smad3/JunD pathways [J].Int Urol Nephrol,2022,54(11):2855-2866.
[13]
Antar SA, Ashour NA, Marawan ME, et al.Fibrosis: types,effects, markers, mechanisms for disease progression, and its relation with oxidative stress, immunity, and inflammation [J].Int J Mol Sci,2023,24(4):4004.
[14]
Huang R, Fu P, Ma L.Kidney fibrosis: from mechanisms to therapeutic medicines [J].Signal Transduct Target Ther,2023,8(1):129.
[15]
Luo H, Yao Y, Wang W, et al.Exploring the therapeutic potential of apabetalone in diabetic kidney disease: bridging preclinical findings with clinical translation [J].Pharmacol Res,2024,208:107362.
[16]
Chen QQ, Liu K, Shi N, et al.Neuraminidase 1 promotes renal fibrosis development in male mice [J].Nat Commun,2023,14(1):1713.
[17]
Qiu D, Song S,Chen N,et al.NQO1 alleviates renal fibrosis by inhibiting the TLR4/NF-κB and TGF-β/Smad signaling pathways in diabetic nephropathy [J].Cell Signal, 2023, 108:110712.
[18]
Pellicena P,Schulman H.CaMKII inhibitors:from research tools to therapeutic agents [J].Front Pharmacol,2014,5:21.
[19]
Feng X,Zhang J,Yang R, et al.The CaMKII inhibitory peptide AIP alleviates renal fibrosis through the TGF-β/Smad and RAF/ERK pathways [J].J Pharmacol Exp Ther, 2023, 386(3):310-322.
[20]
Bezerra Rodrigues Dantas L, Silva ALM, da Silva Júnior CP, et al.Nootkatone inhibits acute and chronic inflammatory responses in mice [J].Molecules,2020,25(9):2181.
[21]
Meeran MFN, Azimullah S, Adeghate E, et al.Nootkatone attenuates myocardial oxidative damage, inflammation, and apoptosis in isoproterenol-induced myocardial infarction in rats[J].Phytomedicine,2021,84:153405.
[22]
Gairola S, Ram C, Syed AM, et al.Nootkatone confers antifibrotic effect by regulating the TGF-β/Smad signaling pathway in mouse model of unilateral ureteral obstruction [J].Eur J Pharmacol,2021,910:174479.
[23]
Li K, Wu L, Chen Y, et al.Cytotoxic and antiproliferative effects of β-mangostin on rat C6 glioma cells depend on oxidative stress induction via PI3K/AKT/mTOR pathway inhibition [J].Drug Des Devel Ther,2020,14:5315-5324.
[24]
Lin CS, Lin CL, Ying TH, et al.β-Mangostin inhibits the metastatic power of cervical cancer cells attributing to suppression of JNK2/AP-1/Snail cascade [J].J Cell Physiol, 2020, 235(11):8446-8460.
[25]
Huang PY, Juan YH, Hung TW, et al.β-Mangostin alleviates renal tubulointerstitial fibrosis via the TGF-β1/JNK signaling pathway [J].Cells,2024,13(20):1701.
[26]
Yang Y, Wang J, Zhang Y, et al.Exosomes derived from mesenchymal stem cells ameliorate renal fibrosis via delivery of miR-186-5p [J].Hum Cell,2022,35(1):83-97.
[27]
Lu Y, Yang L, Chen X, et al.Bone marrow mesenchymal stem cell-derived exosomes improve renal fibrosis by reducing the polarisation of M1 and M2 macrophages through the activation of EP2 receptors [J].IET Nanobiotechnol,2022,16(1):14-24.
[28]
Yin S, Zhou S, Ren D, et al.Mesenchymal stem cell-derived exosomes attenuate epithelial-mesenchymal transition of HK-2 Cells [J].Tissue Eng Part A,2022,28(13-14):651-659.
[29]
Jin J,Qian F,Zheng D,et al.Mesenchymal stem cells attenuate renal fibrosis via exosomes-mediated delivery of microRNA let-7i-5p antagomir [J].Int J Nanomedicine,2021,16:3565-3578.
[30]
Zeng AH, Ou YY, Guo MM, et al.Human embryonic lung fibroblasts treated with artesunate exhibit reduced rates of proliferation and human cytomegalovirus infection in vitro [J].J Thorac Dis,2015,7(7):1151-1157.
[31]
Dolivo D, Weathers P, Dominko T.Artemisinin and artemisinin derivatives as anti-fibrotic therapeutics [J].Acta Pharm Sin B,2021,11(2):322-339.
[32]
Zheng YJ, Li X, Sun L, et al.Therapeutic effect of dihydroartemisinin on pulmonary fibrosis in rats with dust [J].Zhonghua Lao Dong Wei Sheng Zhi Ye Bing Za Zhi, 2019, 37(2):96-103.
[33]
Yang DX, Qiu J, Zhou HH, et al.Dihydroartemisinin alleviates oxidative stress in bleomycin-induced pulmonary fibrosis [J].Life Sci,2018,205:176-183.
[34]
Li Y, Chen S, Tan J, et al.Combination therapy with DHA and BMSCs suppressed podocyte injury and attenuated renal fibrosis by modulating the TGF-β1/Smad pathway in MN mice [J].Ren Fail,2023,45(1):2120821.
[35]
Tu Y,Yang Y,Li Y,et al.Naturally occurring coumestans from plants,their biological activities and therapeutic effects on human diseases [J].Pharmacol Res,2021,169:105615.
[36]
Liang HJ, Suk FM, Wang CK, et al.Osthole, a potential antidiabetic agent, alleviates hyperglycemia in db/db mice [J].Chem Biol Interact,2009,181(3):309-315.
[37]
Li Q, Wang Y, Yan J, et al.Osthole ameliorates early diabetic kidney damage by suppressing oxidative stress, inflammation and inhibiting TGF-β1/Smads signaling pathway [ J ].Int Immunopharmacol,2024,133:112131.
[38]
Kundu S, Ghosh A, Yadav KS, et al.Imperatorin ameliorates kidney injury in diabetic mice by regulating the TGF-β/Smad2/3 signaling axis, epithelial-to-mesenchymal transition, and renal inflammation [J].Eur J Pharmacol,2024,963:176250.
[39]
Yuniati L, Scheijen B, van der Meer LT, et al.Tumor suppressors BTG1 and BTG2: beyond growth control [J].Cell Physiol,2019,234(5):5379-5389.
[40]
Hou CP, Tsui KH, Chang KS, et al.Caffeic acid phenethyl ester inhibits the growth of bladder carcinoma cells by upregulating growth differentiation factor 15 [J].Biomed J,2022,45(5):763-775.
[41]
Coppola V,Musumeci M,Patrizii M,et al.BTG2 loss and miR-21 upregulation contribute to prostate cell transformation by inducing luminal markers expression and epithelial-mesenchymal transition [J].Oncogene,2013,32(14):1843-1853.
[42]
Hoffman MJ, Takizawa A, Jensen ES, et al.Btg2 mutation induces renal injury and impairs blood pressure control in female rats [J].Physiol Genomics,2022,54(7):231-241.
[43]
Hu QD, Wang HL, Liu J, et al.Btg2 promotes focal segmental glomerulosclerosis via Smad3-dependent podocyte-mesenchymal transition [J].Adv Sci (Weinh),2023,10(32): e2304360.
[44]
李思佳, 苏晓乐,王利华.通过抑制Wnt/β-catenin 信号通路延缓肾间质纤维化研究进展[J/OL].中华肾病研究电子杂志,2023,12(4):224-228.
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