

浏览全部资源
扫码关注微信
1.陕西中医药大学,陕西 咸阳 712046
2.陕西省中医医院,西安 710003
Received:24 July 2021,
Published Online:05 December 2021,
Published:05 February 2022
移动端阅览
李姗姗,孙倩,周荣等.中医药调控Wnt/β-catenin信号通路防治肾间质纤维化研究进展[J].中国实验方剂学杂志,2022,28(03):275-282.
LI Shan-shan,SUN Qian,ZHOU Rong,et al.Regulation of Wnt/β-catenin Signaling Pathway in Renal Interstitial Fibrosis by Traditional Chinese Medicine:A Review[J].Chinese Journal of Experimental Traditional Medical Formulae,2022,28(03):275-282.
李姗姗,孙倩,周荣等.中医药调控Wnt/β-catenin信号通路防治肾间质纤维化研究进展[J].中国实验方剂学杂志,2022,28(03):275-282. DOI: 10.13422/j.cnki.syfjx.20220395.
LI Shan-shan,SUN Qian,ZHOU Rong,et al.Regulation of Wnt/β-catenin Signaling Pathway in Renal Interstitial Fibrosis by Traditional Chinese Medicine:A Review[J].Chinese Journal of Experimental Traditional Medical Formulae,2022,28(03):275-282. DOI: 10.13422/j.cnki.syfjx.20220395.
慢性肾脏病(CKD)已经成为世界范围内的公共健康问题,肾间质纤维化(RIF)是各种CKD重要病理特征和最终病理结果。因此,抗纤维化治疗对于延缓CKD进程,改善CKD患者预后具有重要的现实意义。Wnt/
β
-连环蛋白(
β
-catenin)信号传导途径是一种进化保守的发育信号传导途径,在胚胎发育过程中对器官形成,组织稳态和疾病进展发挥着至关重要的作用。越来越多的研究证实,Wnt/
β
-catenin信号通路是多种肾脏疾病的关键信号通路之一,该信号通路的激活与RIF密切相关,通过特异性调控下游靶基因的表达,如成纤维细胞、锌指转录因子1(Snail1),M2巨噬细胞,基质金属蛋白酶-7(MMP-7),纤溶酶原激活物抑制剂-1(PAI-1),肾素-血管紧张素系统(RAS)而促进肾纤维化,而靶向该信号通路,如Klotho,Dickkopf相关蛋白1(DKK1),分泌型卷曲相关蛋白1(Sfrp1),吲哚氰绿-001(ICG-001)可缓解RIF。此外,RIF中西医病理观不谋而合,中医药基于中医虚实夹杂的病因病机,以补虚、泄浊、解毒、祛瘀及标本兼治等法调控促纤维化介质,多靶点、多层次、多途径进行整体调节,抑制Wnt/
β
-catenin信号通路而发挥重要肾保护作用。该文综述了Wnt/
β
-catenin信号通路在RIF中的调控机制及靶向调控该信号通路对肾功能的保护作用,重点探讨了中医药延缓RIF进展的潜在作用,以期为防治RIF提供新靶点和新策略。
Chronic kidney disease (CKD) has become a public health problem worldwide with renal interstitial fibrosis (RIF) serving as the important pathological feature and pathological outcome of various CKD. Therefore, anti-fibrosis therapy has important practical significance for delaying the progression of CKD and improving the prognosis of CKD patients. The Wnt/
β
-catenin signaling pathway is a conserved signaling pathway through evolution, which plays a vital role in organ formation, tissue homeostasis, and disease progression during embryonic development. A growing body of research has confirmed that the Wnt/
β
-catenin signaling pathway is one of the key signaling pathways in a variety of kidney diseases and its activation is closely related to RIF. RIF is aggravated by the specific regulation of the expression of downstream target genes, such as fibroblasts, zinc finger transcription factor 1 (Snail1), M2 macrophages, matrix metalloproteinase-7 (MMP-7), plasminogen activator inhibitor-1 (PAI-1), and renin-angiotensin system(RAS), and relieved by targeting the signaling pathways, such as Klotho, Dickkopf-related protein 1 (DKK1), secreted frizzled-related protein 1 (Sfrp1), and indocyanine green-001. In addition,the pathological view of RIF in traditional Chinese medicine (TCM) coincides with that in western medicine. Based on the etiology and pathogenesis of TCM in the combination of deficiency and excess, TCM regulates fibrosis-promoting mediators by tonifying deficiency, eliminating turbidity, removing the toxin, resolving stasis, and treating both symptoms and root causes in a multi-target, multi-layer, and multi-pathway manner to inhibit the Wnt/
β
-catenin signaling pathway and play an important role in renal protection. Therefore, this study reviewed the regulatory mechanism of the Wnt/
β
-catenin signaling pathway in RIF and the protective effect of targeting this signaling pathway on renal function and discussed the potential role of TCM in delaying the progression of RIF, which is expected to provide new targets and strategies for the prevention and treatment of RIF.
HILL N R , FATOBA S T , OKE J L , et al . Global prevalence of chronic kidney disease-a systematic review and Meta-analysis [J]. PloS One , 2016 , 11 ( 7 ): e158765 .
CHEN L , YANG T , LU D W , et al . Central role of dysregulation of TGF- β /Smad in CKD progression and potential targets of its treatment [J]. Biomed Pharmacother , 2018 , 101 : 670 - 681 .
DUAN J , WANG C , LIU D , et al . Prevalence and risk factors of chronic kidney disease and diabetic kidney disease in Chinese rural residents:a cross-sectional survey [J]. Sci Rep , 2019 , 9 ( 1 ): 10408 .
DJUDJAJ S , BOOR P . Cellular and molecular mechanisms of kidney fibrosis [J]. Mol Aspects Med , 2019 , 65 : 16 - 36 .
JUN J , LAU L F . Resolution of organ fibrosis [J]. J Clin Invest , 2018 , 128 ( 1 ): 97 - 107 .
MARCHETTI B . Wnt/ β -catenin signaling pathway governs a full program for dopaminergic neuron survival,neurorescue and regeneration in the MPTP mouse model of Parkinson's disease [J]. Int J Mol Sci , 2018 , 19 ( 12 ): 3743 .
LI P , ZHANG Y , LIU H . The role of Wnt/ β -catenin pathway in the protection process by dexmedetomidine against cerebral ischemia/reperfusion injury in rats [J]. Life Sci , 2019 , 236 : 116921 .
LIN T , TAO J , CHEN Y , et al . Selenium deficiency leads to changes in renal fibrosis marker proteins and Wnt /β -catenin signaling pathway components [J]. Biol Trace Elem Res , 2021 , doi: 10.1007/s12011-021-02730-1 http://dx.doi.org/10.1007/s12011-021-02730-1 .
ZUO Y , LIU Y . New insights into the role and mechanism of Wnt/ β -catenin signalling in kidney fibrosis [J]. Nephrology(Carlton) , 2018 , 23 ( Suppl 4 ): 38 - 43 .
ZHOU D , TAN R J , FU H , et al . Wnt/ β -catenin signaling in kidney injury and repair:a double-edged sword [J]. Lab Invest , 2016 , 96 ( 2 ): 156 - 167 .
NUSSE R , CLEVERS H . Wnt/ β -catenin signaling,disease,and emerging therapeutic modalities [J]. Cell , 2017 , 169 ( 6 ): 985 - 999 .
SCHUNK S J , FLOEGE J , FLISER D , et al . WNT- β -catenin signalling - a versatile player in kidney injury and repair [J]. Nat Rev Nephrol , 2021 , 17 ( 3 ): 172 - 184 .
KE B , FAN C , YANG L , et al . Matrix metalloproteinases-7 and kidney fibrosis [J]. Front Physiol , 2017 , 8 : 21 .
MIAO J , LIU J , NIU J , et al . Wnt/ β -catenin/RAS signaling mediates age-related renal fibrosis and is associated with mitochondrial dysfunction [J]. Aging Cell , 2019 , 18 ( 5 ): e13004 .
FANG X , HU J , CHEN Y , et al . Dickkopf-3:current knowledge in kidney diseases [J]. Front Physiol , 2020 , 11 : 533344 .
LI Z , ZHOU L , WANG Y , et al . (Pro)renin receptor is an amplifier of Wnt/ β -catenin signaling in kidney injury and fibrosis [J]. J Am Soc Nephrol , 2017 , 28 ( 8 ): 2393 - 2408 .
MIAO J , LIU J , NIU J , et al . Wnt/ β -catenin/RAS signaling mediates age-related renal fibrosis and is associated with mitochondrial dysfunction [J]. Aging Cell , 2019 , 18 ( 5 ): e13004 .
LI S Y , HUANG P H , TARNG D C , et al . Four-and-a-Half LIM domains protein 2 is a coactivator of Wnt signaling in diabetic kidney disease [J]. J Am Soc Nephrol , 2015 , 26 ( 12 ): 3072 - 3084 .
YIU W H , LI Y , LOK S , et al . Protective role of kallistatin in renal fibrosis via modulation of Wnt/ β -catenin signaling [J]. Clin Sci(Lond) , 2021 , 135 ( 3 ): 429 - 446 .
SHI M , TIAN P , LIU Z , et al . MicroRNA-27a targets Sfrp1 to induce renal fibrosis in diabetic nephropathy by activating Wnt/ β -catenin signalling [J]. Biosci Rep , 2020 , doi: 10.1042/BSR20192794 http://dx.doi.org/10.1042/BSR20192794 .
XIE H , MIAO N , XU D , et al . FoxM1 promotes Wnt/ β -catenin pathway activation and renal fibrosis via transcriptionally regulating multi-Wnts expressions [J]. J Cell Mol Med , 2021 , 25 ( 4 ): 1958 - 1971 .
LUO C , ZHOU S , ZHOU Z , et al . Wnt9a promotes renal fibrosis by accelerating cellular senescence in tubular epithelial cells [J]. J Am Soc Nephrol , 2018 , 29 ( 4 ): 1238 - 1256 .
ZHOU D , FU H , ZHANG L , et al . Tubule-derived Wnts are required for fibroblast activation and kidney fibrosis [J]. J Am Soc Nephrol , 2017 , 28 ( 8 ): 2322 - 2336 .
SIMON-TILLAUX N , HERTIG A . Snail and kidney fibrosis [J]. Nephrol Dial Transplant , 2017 , 32 ( 2 ): 224 - 233 .
LIANG G , FANG X , YANG Y , et al . Silencing of CEMIP suppresses Wnt/ β -catenin/Snail signaling transduction and inhibits EMT program of colorectal cancer cells [J]. Acta Histochemica , 2018 , 120 ( 1 ): 56 - 63 .
BAI X , GENG J , ZHOU Z , et al . MicroRNA-130b improves renal tubulointerstitial fibrosis via repression of Snail-induced epithelial-mesenchymal transition in diabetic nephropathy [J]. Sci Rep , 2016 , 6 : 20475 .
TANG P M , NIKOLIC-PATERSON D J , LAN H Y . Macrophages:versatile players in renal inflammation and fibrosis [J]. Nat Rev Nephrol , 2019 , 15 ( 3 ): 144 - 158 .
WONG D , YIU W H , CHAN K W , et al . Activated renal tubular Wnt/ β -catenin signaling triggers renal inflammation during overload proteinuria [J]. Kidney Int , 2018 , 93 ( 6 ): 1367 - 1383 .
FENG Y , LIANG Y , REN J , et al . Canonical Wnt signaling promotes macrophage proliferation during kidney fibrosis [J]. Kidney Dis(Basel) , 2018 , 4 ( 2 ): 95 - 103 .
FENG Y , REN J , GUI Y , et al . Wnt/ β -catenin-promoted macrophage alternative activation contributes to kidney fibrosis [J]. J Am Soc Nephrol , 2018 , 29 ( 1 ): 182 - 193 .
FU H , ZHOU D , ZHU H , et al . Matrix metalloproteinase-7 protects against acute kidney injury by priming renal tubules for survival and regeneration [J]. Kidney Int , 2019 , 95 ( 5 ): 1167 - 1180 .
TAN R J , LI Y , RUSH B M , et al . Tubular injury triggers podocyte dysfunction by β -catenin-driven release of MMP-7 [J]. JCI Insight , 2019 , 4 ( 24 ): e122399 .
LIU Z , TAN R J , LIU Y . The Many faces of matrix metalloproteinase-7 in kidney diseases [J]. Biomolecules , 2020 , 10 ( 6 ): 960 .
ZHOU D , TIAN Y , SUN L , et al . Matrix metalloproteinase-7 is a urinary biomarker and pathogenic mediator of kidney fibrosis [J]. J Am Soc Nephrol , 2017 , 28 ( 2 ): 598 - 611 .
FLEVARIS P , VAUGHAN D . The role of plasminogen activator inhibitor type-1 in fibrosis [J]. Semin Thromb Hemost , 2017 , 43 ( 2 ): 169 - 177 .
RABIEIAN R , BOSHTAM M , ZAREEI M , et al . Plasminogen activator inhibitor type-1 as a regulator of fibrosis [J]. J Cell Biochem , 2018 , 119 ( 1 ): 17 - 27 .
MALIK S A , MODARAGE K , GOGGOLIDOU P . The role of Wnt signalling in chronic kidney disease (CKD) [J]. Genes(Basel) , 2020 , 11 ( 5 ): 496 .
XIAO L , XU B , ZHOU L , et al . Wnt/ β -catenin regulates blood pressure and kidney injury in rats [J]. Biochim Biophys Acta Mol Basis Dis , 2019 , 1865 ( 6 ): 1313 - 1322 .
ZHOU L , LIU Y . Wnt/ β -catenin signaling and renin-angiotensin system in chronic kidney disease [J]. Curr Opin Nephrol Hypertens , 2016 , 25 ( 2 ): 100 - 106 .
HUANG Y , LIU L , LIU A . Dickkopf-1:current knowledge and related diseases [J]. Life Sci , 2018 , 209 : 249 - 254 .
JOHNSON B G , REN S , KARACA G , et al . Connective tissue growth factor domain 4 amplifies fibrotic kidney disease through activation of LDL receptor-related protein 6 [J]. J Am Soc Nephrol , 2017 , 28 ( 6 ): 1769 - 1782 .
KLAVDIANOU K , LIOSSIS S , DAOUSSIS D . Dkk1:A key molecule in joint remodelling and fibrosis [J]. Mediterr J Rheumatol , 2017 , 28 ( 4 ): 174 - 182 .
XIA J , CAO W . Epigenetic modifications of Klotho expression in kidney diseases [J]. J Mol Med , 2021 , 99 ( 5 ): 581 - 592 .
MUÑOZ-CASTAÑEDA J R , RODELO-HAAD C , PENDON-RUIZ DE MIER M V , et al . Klotho/FGF23 and Wnt signaling as important players in the comorbidities associated with chronic kidney disease [J]. Toxins , 2020 , 12 ( 3 ): 185 .
HSUEH Y C , HODGKINSON C P , GOMEZ J A . The role of Sfrp and DKK proteins in cardiomyocyte development [J]. Physiol Rep , 2021 , 9 ( 3 ): e14678 .
HENDERSON J , WILKINSON S , PRZYBORSKI S , et al . microRNA27a-3p mediates reduction of the Wnt antagonist sFRP-1 in systemic sclerosis [J]. Epigenetics , 2020 , 16 ( 7 ): 808 - 817 .
AKCORA B Ö , STORM G , BANSAL R . Inhibition of canonical Wnt signaling pathway by β- catenin/CBP inhibitor ICG-001 ameliorates liver fibrosis in vivo through suppression of stromal CXCL12 [J]. Biochim Biophys Acta Mol Basis Dis , 2018 , 1864 ( 3 ): 804 - 818 .
ZHOU L , LI Y , HAO S , et al . Multiple genes of the renin-angiotensin system are novel targets of Wnt/ β -catenin signaling [J]. J Am Soc Nephrol , 2015 , 26 ( 1 ): 107 - 120 .
FLOEGE J . Antagonism of canonical Wnt/ β -catenin signaling:taking RAS blockade to the next level? [J]. J Am Soc Nephrol , 2015 , 26 ( 1 ): 3 - 5 .
沈金峰 , 胡芳 , 黄伟 , 等 . 肾纤维化中医病机与Wnt/ β -catenin信号通路的关系 [J]. 中国中医基础医学杂志 , 2018 , 24 ( 11 ): 1548 - 1549 .
沈金峰 , 罗富里 , 胡芳 , 等 . 从“Wnt/ β -catenin-伏毒”论肾纤维化病因病机 [J]. 中华中医药学刊 , 2019 , 37 ( 1 ): 70 - 72 .
ZHAO M , YU Y , WANG R , et al . Mechanisms and efficacy of Chinese herbal medicines in chronic kidney disease [J]. Front Pharmacol , 2021 , 11 : 619201 .
俞曼殊 . 黄芪调控Wnt/ β -catenin通路干预腹膜间皮细胞表型转化的机制研究 [D]. 南京 : 南京中医药大学 , 2019 .
邓文超 , 方敬爱 . 黄芪对糖尿病肾病大鼠肾间质Wnt/ β -catenin及TGF- β 1 信号通路表达的影响 [J]. 中国中西医结合肾病杂志 , 2012 , 13 ( 7 ): 571 - 574 .
周欢 . 枸杞多糖在UUO大鼠肾间质纤维化Wnt/ β -catenin信号通路中的作用及机制研究 [D]. 银川 : 宁夏医科大学 , 2018 .
常保超 , 陈卫东 , 张燕 , 等 . 白芍总苷对2型糖尿病大鼠肾组织Wnt/ β -catenin信号通路表达的影响 [J]. 中国中药杂志 , 2014 , 39 ( 19 ): 3829 - 3835 .
CHANG B , CHEN W , ZHANG Y , et al . Tripterygium wilfordii mitigates hyperglycemia-induced upregulated Wnt/ β -catenin expression and kidney injury in diabetic rats [J]. Exp Ther Med , 2018 , 15 ( 4 ): 3874 - 3882 .
肖伟伟 , 奚悦 . 白藜芦醇对糖尿病肾病大鼠Wnt/ β -catenin和TGF- β 1 -Smad2/3信号通路的影响 [J]. 中成药 , 2019 , 41 ( 12 ): 3033 - 3038 .
张涛 , 朱小军 , 陈慧 , 等 . 大黄酸对高糖诱导人肾小球系膜细胞Wnt、 β -catenin蛋白及TGF- β 1 表达的影响 [J]. 环球中医药 , 2015 , 8 ( S2 ): 155 - 156 .
CHEN D Q , FENG Y L , CAO G , et al . Natural products as a source for antifibrosis therapy [J]. Trends Pharmacol Sci , 2018 , 39 ( 11 ): 937 - 952 .
WANG M , CHEN D Q , CHEN L , et al . Novel inhibitors of the cellular renin-angiotensin system components,poricoic acids,target Smad3 phosphorylation and Wnt/ β -catenin pathway against renal fibrosis [J]. Br J Pharmacol , 2018 , 175 ( 13 ): 2689 - 2708 .
WANG M , CHEN D Q , CHEN L , et al . Novel RAS inhibitors poricoic acid ZG and poricoic acid ZH attenuate renal fibrosis via a Wnt/ β -catenin pathway and targeted phosphorylation of Smad3 signaling [J]. J Agric Food Chem , 2018 , 66 ( 8 ): 1828 - 1842 .
WANG M , HU H H , CHEN Y Y , et al . Novel poricoic acids attenuate renal fibrosis through regulating redox signalling and aryl hydrocarbon receptor activation [J]. Phytomedicine , 2020 , 79 : 153323 .
刘娇娇 , 孟祥燕 , 陈凤 , 等 . 丹参对血管紧张素Ⅱ致肾小球系膜细胞Wnt/ β -catenin信号通路活化干预的影响 [J]. 中医药学报 , 2018 , 46 ( 2 ): 44 - 49 .
王曼 , 王新宇 , 陈叶香 , 等 . 丹酚酸B干预肾间质纤维化Wnt/ β -catenin信号通路的研究 [J]. 中药新药与临床药理 , 2016 , 27 ( 5 ): 602 - 607 .
SHATI A A , ALFAIFI M Y . Salidroside protects against diabetes mellitus‐induced kidney injury and renal fibrosis by attenuating TGF‐ β 1 and Wnt1/3a/ β ‐catenin signalling [J]. Clin Exp Pharmacol Physiol , 2020 , 47 ( 10 ): 1692 - 1704 .
ZHANG Q , XIAO X , ZHENG J , et al . Qishen Yiqi dripping pill protects against diabetic nephropathy by inhibiting the Wnt/ β -catenin and transforming growth factor- β /Smad signaling pathways in rats [J]. Front Physiol , 2021 , 11 : 613324 .
ZHANG X , FANG J , CHEN Z , et al . Qingshen Buyang formula attenuates renal fibrosis in 5/6 nephrectomized rats via inhibiting EMT and Wnt/ β -catenin pathway [J]. Evid Based Complement Alternat Med , 2019 , doi: 10.1155/2019/5370847 http://dx.doi.org/10.1155/2019/5370847 .
LA L , WANG L , QIN F , et al . Zhen-wu-tang ameliorates adenine-induced chronic renal failure in rats:regulation of the canonical Wnt4/beta-catenin signaling in the kidneys [J]. J Ethnopharmacol , 2018 , 219 : 81 - 90 .
刘武 , 丁宁 , 姜赫 , 等 . miRNA-139调控Wnt/ β -catenin信号通路探讨建中补肾消癥汤抗肾间质纤维化机制 [J]. 中国实验方剂学杂志 , 2021 , 27 ( 4 ): 47 - 55 .
李荣荣 , 马华 , 田树杰 , 等 . 芪红通瘀饮对肾间质纤维化大鼠肾组织Wnt/ β -catenin信号通路的影响 [J]. 中华中医药杂志 , 2020 , 35 ( 4 ): 1755 - 1759 .
黄仁发 , 梁群卿 , 邓鸣 , 等 . 加味六味地黄汤对UUO大鼠肾组织Wnt4/ β -catenin信号通路介导调控FGF-23的影响 [J]. 中国中西医结合肾病杂志 , 2019 , 20 ( 4 ): 285 - 289 .
罗婷 , 程锦国 , 姜程曦 , 等 . 清化固肾排毒颗粒对肾纤维化大鼠Wnt通路Wnt1和 β -catenin表达的影响 [J]. 中草药 , 2016 , 47 ( 6 ): 955 - 962 .
GUO Q , ZHONG W , DUAN A , et al . Protective or deleterious role of Wnt/beta-catenin signaling in diabetic nephropathy:an unresolved issue [J]. Pharmacol Res , 2019 , 144 : 151 - 157 .
0
Views
23
下载量
2
CSCD
Publicity Resources
Related Articles
Related Author
Related Institution
京公网安备11010802024621