中医药改善糖尿病肾脏疾病间质纤维化的作用机制研究现状

doi:10.16138/j.1673-6087.2025.01.08

摘要/Abstract

摘要：

糖尿病肾脏疾病(diabetic kidney disease，DKD)是由高血糖所致的慢性肾脏疾病，属于糖尿病常见的微血管并发症之一。间质纤维化作为其显著病理特征，是导致肾功能损伤的关键因素，其病理演变涉及代谢异常、血流动力学紊乱、炎症反应、细胞信号通路激活、表观遗传调控和细胞自噬等多重机制。本文通过检索多个数据库（Pubmed、Web of Science、中国知网、万方、维普等），对中医药改善DKD间质纤维化的作用机制相关文献进行整理分析。研究提示中医药可能通过多成分、多靶点、多途径延缓DKD间质纤维化。随着对DKD间质纤维化发病机制的进一步深入研究和中医药作用机制的不断阐明，中医药有望为DKD的防治提供更有效的策略。

关键词: 糖尿病肾脏疾病, 间质纤维化, 中医药

Abstract:

Diabetes kidney disease (DKD) is a chronic kidney disease caused by hyperglycemia, which is one of the common microvascular complications of diabetes. As one of the significant pathological features, interstitial fibrosis is a key factor leading to renal dysfunction. Its pathological evolution involves multiple mechanisms such as metabolic abnormalities, hemodynamic disorders, inflammatory responses, activation of cellular signaling pathways, epigenetic regulation, and cellular autophagy. This article sorted and analyzed the relevant research on the mechanism of action of traditional Chinese medicine (TCM) in improving interstitial fibrosis of DKD through searching multiple databases (Pubmed, Web of Science, CNKI, WANFANG, VIP databases, etc.). Studies have shown that treatment of TCM may delay DKD interstitial fibrosis through its multi-component, multi-target and multi pathway. In the future, with further in-depth research on the pathogenesis of DKD interstitial fibrosis and continuous clarification of the mechanism of action of TCM, TCM is expected to provide more effective strategies for the prevention and treatment of DKD.

Key words: Diabetic kidney disease, Interstitial fibrosis, Traditional Chinese medicine

中图分类号:

R587

严佳怡, 马骏, 钟逸斐, 张先闻. 中医药改善糖尿病肾脏疾病间质纤维化的作用机制研究现状[J]. 内科理论与实践, 2025, 20(01): 38-45.

YAN Jiayi, MA Jun, ZHONG Yifei, ZHANG Xianwen. Current research status on mechanism of action of traditional Chinese medicine in improving interstitial fibrosis of diabetes kidney disease[J]. Journal of Internal Medicine Concepts & Practice, 2025, 20(01): 38-45.

参考文献 66

[1]	Afkarian M, Zelnick LR, Hall YN, et al. Clinical manifestations of kidney disease among US adults with diabetes, 1988-2014[J]. JAMA, 2016, 316(6):602-610. doi: 10.1001/jama.2016.10924 pmid: 27532915
[2]	Leoncini G, Viazzi F, De Cosmo S, et al. Blood pressure reduction and RAAS inhibition in diabetic kidney disease: therapeutic potentials and limitations[J]. J Nephrol, 2020, 33(5):949-963.
[3]	Noonin C, Thongboonkerd V. Curcumin prevents high glucose-induced stimulatory effects of renal cell secretome on fibroblast activation via mitigating intracellular free radicals and TGF-β secretion[J]. Biomed Pharmacother, 2024,174:116536.
[4]	Pan Y, Zhang Y, Li J, et al. A proteoglycan isolated from Ganoderma lucidum attenuates diabetic kidney disease by inhibiting oxidative stress-induced renal fibrosis both in vitro and in vivo[J]. J Ethnopharmacol, 2023,310:116405.
[5]	赵茜, 吴佳丽, 黄梓越, 等. 糖尿病肾脏疾病的发病机制研究进展[J]. 临床肾脏病杂志, 2020, 20(1):77-82.
[6]	Meng XM, Nikolic-Paterson DJ, Lan HY. TGF-β: the master regulator of fibrosis[J]. Nat Rev Nephrol, 2016, 12(6):325-338.
[7]	DCCT/EDIC Research Group. Kidney disease and related findings in the diabetes control and complications trial/epidemiology of diabetes interventions and complications study[J]. Diabetes Care, 2014, 37(1):24-30. doi: 10.2337/dc13-2113 pmid: 24356594
[8]	American Diabetes Association. Introduction: medical standards in diabetes-2022[J]. Diabetes Care, 2022,45 Suppl 1:S1-S2.
[9]	Ricciardi CA, Gnudi L. Kidney disease in diabetes: from mechanisms to clinical presentation and treatment strategies[J]. Metabolism, 2021,124:154890.
[10]	Fang H, Li X, Lin D, et al. Inhibition of intrarenal PRR-RAS pathway by ganoderma lucidum polysaccharide peptides in proteinuric nephropathy[J]. Int J Biol Macromol, 2023, 253(Pt 7):127336.
[11]	Yang T, Xu C. Physiology and pathophysiology of the intrarenal renin-angiotensin system: an update[J]. J Am Soc Nephrol, 2017, 28(4):1040-1049.
[12]	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.
[13]	Wang M, Chen DQ, 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.
[14]	Chen H, Yang T, Wang MC, et al. Novel RAS inhibitor 25-O-methylalisol F attenuates epithelial-to-mesenchymal transition and tubulo-interstitial fibrosis by selectively inhibiting TGF-β-mediated Smad3 phosphorylation[J]. Phytomedicine, 2018,42:207-218.
[15]	Hadden MJ, Advani A. Histone deacetylase inhibitors and diabetic kidney disease[J]. Int J Mol Sci, 2018, 19(9):2630.
[16]	Feng Y, Guo F, Mai H, et al. Pterostilbene, a bioactive component of blueberries, alleviates renal interstitial fibrosis by inhibiting macrophage-myofibroblast transition[J]. Am J Chin Med, 2020, 48(7):1715-1729.
[17]	Sari DCR, Budiharjo S, Afifah H, et al. Centella asiatica extract attenuates kidney fibrosis through reducing mesenchymal transition and inflammation in ureteral ligation model in mice[J]. Front Pharmacol, 2021,12:621894.
[18]	Xiaomeng G, Panpan Q, Jingyue C, et al. Huoxue Jiedu Huayu recipe inhibits macrophage-secreted vascular endothelial growth factor-a on angiogenesis and alleviates renal fibrosis in the contralateral kidneys of unilateral ureteral obstruction rats[J]. J Tradit Chin Med, 2024, 44(3):458-467. doi: 10.19852/j.cnki.jtcm.20240423.005
[19]	Majumder S, Hadden MJ, Thieme K, et al. Dysregulated expression but redundant function of the long non-coding RNA HOTAIR in diabetic kidney disease[J]. Diabetologia, 2019, 62(11):2129-2142. doi: 10.1007/s00125-019-4967-1 pmid: 31399844
[20]	Zhou D, Liu Y. Renal fibrosis in 2015: Understanding the mechanisms of kidney fibrosis[J]. Nat Rev Nephrol. 2016, 12(2):68-70. doi: 10.1038/nrneph.2015.215 pmid: 26714578
[21]	Meng XM, Tang PM, Li J, et al. TGF-β/Smad signaling in renal fibrosis[J]. Front Physiol, 2015,6:82.
[22]	Xia Y, Jiang H, Chen J, et al. Low dose Taxol ameliorated renal fibrosis in mice with diabetic kidney disease by downregulation of HIPK2[J]. Life Sci, 2023,320:121540.
[23]	赵海霞, 曹盼盼, 刘林昊, 等. 槲皮素对1型糖尿病肾病肾小管上皮细胞间质转分化的作用[J]. 天津中医药, 2022, 39(5):663-667.
[24]	Geng XQ, Ma A, He JZ, et al. Ganoderic acid hinders renal fibrosis via suppressing the TGF-β/Smad and MAPK signaling pathways[J]. Acta Pharmacol Sin, 2020, 41(5):670-677.
[25]	He Y, Sun MM, Zhang GG, et al. Targeting PI3K/Akt signal transduction for cancer therapy[J]. Signal Transduct Target Ther, 2021, 6(1):425.
[26]	Liu R, Chen Y, Liu G, et al. PI3K/AKT pathway as a key link modulates the multidrug resistance of cancers[J]. Cell Death Dis, 2020, 11(9):797. doi: 10.1038/s41419-020-02998-6 pmid: 32973135
[27]	Tian LY, Smit DJ, Jücker M. The role of PI3K/AKT/mTOR signaling in hepatocellular carcinoma metabolism[J]. Int J Mol Sci, 2023, 24(3):2652.
[28]	Burke JE, Triscott J, Emerling BM, et al. Beyond PI3Ks: targeting phosphoinositide kinases in disease[J]. Nat Rev Drug Discov, 2023, 22(5):357-386.
[29]	Liu PY, Hong KF, Liu YD, et al. Total flavonoids of Astragalus protects glomerular filtration barrier in diabetic kidney disease[J]. Chin Med, 2024, 19(1):27.
[30]	Wang Z, Jian G, Chen T, et al. The Qi-Bang-Yi-Shen formula ameliorates renal dysfunction and fibrosis in rats with diabetic kidney disease via regulating PI3K/AKT, ERK and PPARγ signaling pathways[J]. Eur J Histochem, 2023, 67(1):3648.
[31]	杨鹏, 刘铜华, 吴丽丽, 等. 中药基于p38 MAPK信号通路干预糖尿病肾病的研究进展[J]. 中国实验方剂学杂志, 2023, 29(11):212-223.
[32]	高子涵, 李瑞芳, 吕行直, 等. 山药多糖对糖尿病肾病小鼠肾功能和醛糖还原酶通路的影响[J]. 中药材, 2019, 42(3):643-646.
[33]	Qiao Y, Gao K, Wang Y, et al. Resveratrol ameliorates diabetic nephropathy in rats through negative regulation of the p38 MAPK/TGF-β1 pathway[J]. Exp Ther Med, 2017, 13(6):3223-3230. doi: 10.3892/etm.2017.4420 pmid: 28588674
[34]	Perdigoto CN, Bardin AJ. Sending the right signal: Notch and stem cells[J]. Biochim Biophys Acta, 2013, 1830(2):2307-2322. doi: 10.1016/j.bbagen.2012.08.009 pmid: 22917651
[35]	Park JS, Kim SH, Kim K, et al. Inhibition of notch signalling ameliorates experimental inflammatory arthritis[J]. Ann Rheum Dis, 2015, 74(1):267-274.
[36]	Kopan R, Ilagan MX. The canonical Notch signaling pathway: unfolding the activation mechanism[J]. Cell, 2009, 137(2):216-233. doi: 10.1016/j.cell.2009.03.045 pmid: 19379690
[37]	Bi P, Kuang S. Notch signaling as a novel regulator of metabolism[J]. Trends Endocrinol Metab, 2015, 26(5):248-255.
[38]	Matsui F, Meldrum KK. The role of the Janus kinase family/signal transducer and activator of transcription signaling pathway in fibrotic renal disease[J]. J Surg Res, 2012, 178(1):339-345. doi: 10.1016/j.jss.2012.06.050 pmid: 22883438
[39]	Zheng C, Huang L, Luo W, et al. Inhibition of STAT3 in tubular epithelial cells prevents kidney fibrosis and nephropathy in STZ-induced diabetic mice[J]. Cell Death Dis, 2019, 10(11):848. doi: 10.1038/s41419-019-2085-0 pmid: 31699972
[40]	Naso LG, Valcarcel M, Roura-Ferrer M, et al. Promising antioxidant and anticancer (human breast cancer) oxidovanadium(Ⅳ) complex of chlorogenic acid[J]. J Inorg Biochem, 2014,135:86-99.
[41]	Yang XY, Jiang D, Wang YZ, et al. Chlorogenic acid alleviates renal fibrosis by reducing lipid accumulation in diabetic kidney disease through suppressing the Notch1 and Stat3 signaling pathway[J]. Ren Fail, 2024, 46(2):2371988.
[42]	Zhu Q, Zeng J, Li J, et al. Effects of compound centella on oxidative stress and Keap1-Nrf2-ARE pathway expression in diabetic kidney disease rats[J]. Evid Based Complement Alternat Med, 2020,2020:9817932.
[43]	Adelusi TI, Du L, Hao M, et al. Keap1/Nrf2/ARE signaling unfolds therapeutic targets for redox imbalanced-mediated diseases and diabetic nephropathy[J]. Biomed Pharmacother, 2020,123:109732.
[44]	Liu Y, Wang S, Jin G, et al. Network pharmacology-based study on the mechanism of ShenKang injection in diabetic kidney disease through Keap1/Nrf2/Ho-1 signaling pathway[J]. Phytomedicine, 2023,118:154915.
[45]	El Ouarrat D, Isaac R, Lee YS, et al. TAZ is a negative regulator of PPARγ activity in adipocytes and TAZ deletion improves insulin sensitivity and glucose tolerance[J]. Cell Metab, 2020, 31(1):162-173. doi: S1550-4131(19)30558-3 pmid: 31708444
[46]	Hernandez-Quiles M, Broekema MF, Kalkhoven E. PPARgamma in metabolism, immunity, and cancer: unified and diverse mechanisms of action[J]. Front Endocrinol (Lausanne), 2021,12:624112.
[47]	Lecarpentier Y, Claes V, Vallée A, et al. Interactions between PPAR gamma and the canonical Wnt/Beta-Catenin pathway in type 2 diabetes and colon cancer[J]. PPAR Res, 2017,2017:5879090.
[48]	Sui Z, Sui D, Li M, et al. Ginsenoside Rg3 has effects comparable to those of ginsenoside re on diabetic kidney disease prevention in db/db mice by regulating inflammation, fibrosis and PPARγ[J]. Mol Med Rep, 2023, 27(4):84.
[49]	温智勇, 夏金金, 江伟强. 肾康丸联合舒洛地特软胶囊治疗气阴两虚型糖尿病肾病疗效及对患者尿微小RNA-192表达的影响[J]. 河北中医, 2020, 42(7):1028-1033.
[50]	Zhou W, Chen MM, Liu HL, et al. Dihydroartemisinin suppresses renal fibrosis in mice by inhibiting DNA-methyltransferase 1 and increasing Klotho[J]. Acta Pharmacol Sin, 2022, 43(10):2609-2623. doi: 10.1038/s41401-022-00898-3 pmid: 35347248
[51]	Majumder S, Hadden MJ, Thieme K, et al. Dysregulated expression but redundant function of the long non-coding RNA HOTAIR in diabetic kidney disease[J]. Diabetologia, 2019, 62(11):2129-2142. doi: 10.1007/s00125-019-4967-1 pmid: 31399844
[52]	Qin W, Chung AC, Huang XR, et al. TGF-β/Smad3 signaling promotes renal fibrosis by inhibiting miR-29[J]. J Am Soc Nephrol, 2011, 22(8):1462-1474. doi: 10.1681/ASN.2010121308 pmid: 21784902
[53]	Yang J, Shen Y, Yang X, et al. Silencing of long noncoding RNA XIST protects against renal interstitial fibrosis in diabetic nephropathy via microRNA-93-5p-mediated inhibition of CDKN1A[J]. Am J Physiol Renal Physiol, 2019, 317(5):F1350-F1358.
[54]	Zhang Y, Deng Y, Yang Y, et al. Polysaccharides from Dendrobium officinale delay diabetic kidney disease interstitial fibrosis through LncRNA XIST/TGF-β1[J]. Biomed Pharmacother, 2024,175:116636.
[55]	Forbes JM, Thorburn DR. Mitochondrial dysfunction in diabetic kidney disease[J]. Nat Rev Nephrol, 2018, 14(5):291-312. doi: 10.1038/nrneph.2018.9 pmid: 29456246
[56]	Wang Y, Yu L, Li Y, et al. Supplemented Gegen Qinlian decoction formula attenuates podocyte mitochondrial fission and renal fibrosis in diabetic kidney disease by inhibiting TNF-α-mediated necroptosis, compared with empagliflozin[J]. J Ethnopharmacol, 2024,334:118572.
[57]	Hu H, Li W, Hao Y, et al. Baicalin ameliorates renal fibrosis by upregulating CPT1α-mediated fatty acid oxidation in diabetic kidney disease[J]. Phytomedicine, 2024,122:155162.
[58]	宋宜耘, 于慧, 李宪花. 线粒体损伤与糖尿病肾脏疾病的研究进展[J]. 临床肾脏病杂志, 2023, 23(10):858-862.
[59]	Liu T, Yang Q, Zhang X, et al. Quercetin alleviates kidney fibrosis by reducing renal tubular epithelial cell senescence through the SIRT1/PINK1/mitophagy axis[J]. Life Sci, 2020,257:118116.
[60]	Zeisberg M, Neilson EG. Biomarkers for epithelial-mesenchymal transitions[J]. J Clin Invest, 2009, 119(6):1429-1437. doi: 10.1172/JCI36183 pmid: 19487819
[61]	Kalluri R, Neilson EG. Epithelial-mesenchymal transition and its implications for fibrosis[J]. J Clin Invest, 2003, 112(12):1776-1784. doi: 10.1172/JCI20530 pmid: 14679171
[62]	Li J, Pang Q, Huang X, et al. 2-dodecyl-6-methoxycyclohexa-2, 5-diene-1, 4-dione isolated from averrhoa carambola L. root inhibits high glucose-induced EMT in HK-2 cells through targeting the regulation of miR-21-5p/Smad7 signaling pathway[J]. Biomed Pharmacother, 2024,172:116280.
[63]	曹延萍. 内质网应激在糖尿病肾损害过程中的作用及其机制研究[D]. 石家庄: 河北医科大学, 2011.
[64]	Xu S, He L, Ding K, et al. Tanshinone ⅡA ameliorates streptozotocin-induced diabetic nephropathy, partly by attenuating PERK pathway-induced fibrosis[J]. Drug Des Devel Ther, 2020,14:5773-5782.
[65]	Zhang L, Yang F. Tanshinone ⅡA improves diabetes-induced renal fibrosis by regulating the miR-34-5p/Notch1 axis[J]. Food Sci Nutr, 2022, 10(11):4019-4040.
[66]	Song L, Zhang W, Tang SY, et al. Natural products in traditional Chinese medicine: molecular mechanisms and therapeutic targets of renal fibrosis and state-of-the-art drug delivery systems[J]. Biomed Pharmacother, 2024,170:116039.