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1.南方医科大学 中医药学院,广州 510515
2.南方医科大学 珠江医院,广州 510280
Received:05 November 2024,
Accepted:27 December 2024,
Published Online:31 December 2024,
Published:20 April 2025
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谢家润,林浩裕,陈茜等.HIF-1α在糖尿病肾病中的机制研究及中医药改善作用的研究进展[J].中国实验方剂学杂志,2025,31(08):287-293.
XIE Jiarun,LIN Haoyu,CHEN Xi,et al.Mechanism of HIF-1α in Diabetic Nephropathy and Improvement Effect of Traditional Chinese Medicine: A Review[J].Chinese Journal of Experimental Traditional Medical Formulae,2025,31(08):287-293.
谢家润,林浩裕,陈茜等.HIF-1α在糖尿病肾病中的机制研究及中医药改善作用的研究进展[J].中国实验方剂学杂志,2025,31(08):287-293. DOI: 10.13422/j.cnki.syfjx.20250106.
XIE Jiarun,LIN Haoyu,CHEN Xi,et al.Mechanism of HIF-1α in Diabetic Nephropathy and Improvement Effect of Traditional Chinese Medicine: A Review[J].Chinese Journal of Experimental Traditional Medical Formulae,2025,31(08):287-293. DOI: 10.13422/j.cnki.syfjx.20250106.
近年来,糖尿病肾病(DN)已成为全球范围内一个日益严峻的健康挑战,其发病率与死亡率正迅速攀升,且患者年龄渐趋于年轻化。DN不仅伴随着广泛的肾脏病理改变,如肾脏肥大、炎症细胞浸润、系膜基质扩张及基底膜增厚等,更是导致糖尿病患者发生终末期肾病和死亡的主要原因,因此,探索DN的预防与治疗新策略显得尤为迫切。DN的发病机制错综复杂,当前研究多聚焦于代谢与血流动力学因素等多因素相互作用,诸如缺氧、炎症反应及纤维化过程等。值得注意的是,缺氧在DN的启动与进展中扮演着举足轻重的角色。缺氧诱导因子-1
α
(HIF-1
α
),作为一种在缺氧细胞中普遍存在的关键调节蛋白,对细胞代谢、血管新生、氧化应激反应及细胞凋亡等多个生理病理过程具有深远影响。而中医药以其独特的理论体系与治疗方法,在应对缺氧性疾病方面展现出了显著优势,能通过调节HIF-1
α
及其下游信号分子的表达水平,发挥抗炎、抗氧化和抗纤维化的作用,延缓DN的进展,对于药物研发和DN的早期防治具有积极的临床意义。
In recent years, diabetic nephropathy (DN) has become an increasingly serious health challenge worldwide, and its morbidity and mortality rates are rapidly increasing. The patients suffering from the disease tend to be younger. DN is not only accompanied by a wide range of renal pathological changes, such as renal hypertrophy, inflammatory cell infiltration, expansion of the tethered membrane stroma, and thickening of the basement membrane but is also the main cause of end-stage renal disease and death in patients with diabetes mellitus. Therefore, it is particularly urgent to explore new strategies for the prevention and treatment of DN. The pathogenesis of DN is intricate and complex, with current research focusing on multifactorial interactions between metabolic and hemodynamic factors, such as hypoxia, inflammatory responses, and fibrotic processes. Notably, hypoxia plays a pivotal role in the initiation and progression of DN. Hypoxia-inducible factor (HIF-1
α
), as a key regulatory protein commonly found in hypoxic cells, has a profound impact on various physiological and pathological processes, such as cell metabolism, vascular neogenesis, oxidative stress, and apoptosis. With its unique theoretical system and therapeutic approach, traditional Chinese medicine has demonstrated significant advantages in coping with hypoxic diseases and can slow down the progression of DN by regulating the expression level of HIF-1
α
and its downstream signaling molecules and exerting anti-inflammatory, antioxidant, and antifibrotic effects, which has positive clinical significance for drug development and early prevention and treatment of DN.
WANG H , LIU D , ZHENG B , et al . Emerging role of ferroptosis in diabetic kidney disease:Molecular mechanisms and therapeutic opportunities [J]. Int J Biol Sci , 2023 , 19 ( 9 ): 2678 - 2694 .
SAEEDI P , PETERSOHN I , SALPEA P , et al . Global and regional diabetes prevalence estimates for 2019 and projections for 2030 and 2045: Results from the International Diabetes Federation Diabetes Atlas, 9(th) edition [J]. Diabetes Res Clin Pract , 2019 , 157 : 107843 .
TANG A , ZHANG Y , WU L , et al . Klotho's impact on diabetic nephropathy and its emerging connection to diabetic retinopathy [J]. Front Endocrinol(Lausanne) , 2023 , 14 : 1180169 .
INADA A , INADA O , YASUNAMI Y , et al . Amelioration of murine diabetic nephropathy with a SGLT2 inhibitor is associated with suppressing abnormal expression of hypoxia-inducible factors [J]. Am J Pathol , 2022 , 192 ( 7 ): 1028 - 1052 .
NIU G , ZHOU M , WANG F , et al . Marein ameliorates Ang Ⅱ/hypoxia-induced abnormal glucolipid metabolism by modulating the HIF-1 α /PPAR α / γ pathway in H9c2 cells [J]. Drug Dev Res , 2021 , 82 ( 4 ): 523 - 532 .
WANG S , QIN S , CAI B , et al . Promising therapeutic mechanism for Chinese herbal medicine in ameliorating renal fibrosis in diabetic nephropathy [J]. Front Endocrinol(Lausanne) , 2023 , 14 : 932649 .
RUAN Y , LING J , YE F , et al . Paeoniflorin alleviates CFA-induced inflammatory pain by inhibiting TRPV1 and succinate/SUCNR1-HIF-1 α /NLPR3 pathway [J]. Int Immunopharmacol , 2021 , 101 ( Pt B ): 108364 .
CHANG J , ZHENG J , GAO X , et al . Tangshen Weining formula prevents dia betic nephropathy by protecting podocytes through the SIRT1/HIF-1 α pathway [J]. Front Endocrinol(Lausanne) , 2022 , 13 : 888611 .
SEMENZA G L , WANG G L . A nuclear factor induced by hypoxia via de novo protein synthesis binds to the human erythropoietin gene enhancer at a site required for transcriptional activation [J]. Mol Cell Biol , 1992 , 12 ( 12 ): 5447 - 5454 .
LIAO Q , DENG H , WANG Z , et al . Deletion of prolyl hydroxylase domain-containing enzyme 3(PHD3) in zebrafish facilitates hypoxia tolerance [J]. J Biol Chem , 2023 , 299 ( 12 ): 105420 .
ZHANG Y , YANG Y , HU X , et al . RAS protein activator-like 2 (RASAL2) initiates peritubular capillary rarefaction in hypoxic renal interstitial fibrosis [J]. Transl Res , 2024 , 269 : 14 - 30 .
WANG D , WANG F , HUANG Y , et al . TSLP/TSLPR promotes renal fibrosis by activating STAT3 in renal fibroblasts [J]. Int Immunopharmacol , 2023 , 121 : 110430 .
汤蜜 , 李沁芸 , 李少斌 , 等 . 含羞草素对糖尿病大鼠肾脏缺氧损伤及HIF/PHD轴的影响 [J]. 遵义医学院学报 , 2019 , 42 ( 5 ): 527 - 533 .
TANG M , LI Q Y , LI S B , et al . Effects of L -mimosine on renal hypoxia and HIF/PHD axis in diabetic rats [J]. J Zunyi Med Univ , 2019 , 42 ( 5 ): 527 - 533 .
GUAN Z , JIN X , GUAN Z , et al . The gut microbiota metabolite capsiate regulate SLC2A1 expression by targeting HIF-1 α to inhibit knee osteoarthritis-induced ferroptosis [J]. Aging Cell , 2023 , 22 ( 6 ): e13807 .
IACOBINI C , VITALE M , HAXHI J , et al . Mutual regulation between redox and hypoxia-inducible factors in cardiovascular and renal complications of diabetes [J]. Antioxidants(Basel) , 2022 , 11 ( 11 ): 2183 .
JATHO A , ZIESENISS A , BRECHTEL-CURTH K , et al . The HIF α -stabilizing drug roxadustat increases the number of renal epo-producing Sca- 1 + cells [J]. Cells , 2022 , 11 ( 4 ): 753 .
WU M , CHEN W , MIAO M , et al . Anti-anemia drug FG4592 retards the AKI-to-CKD transition by improving vascular regeneration and antioxidative capability [J]. Clin Sci(Lond) , 2021 , 135 ( 14 ): 1707 - 1726 .
ZHENG X , LIU D . Adiponectin alleviates the symptoms of ischemic renal disease by inhibiting renal cell apoptosis [J]. Life Sci , 2021 , 265 : 118825 .
SAMAAN E , RAMADAN N M , ABDULAZIZ H , et al . DPP-4i versus SGLT2i as modulators of PHD3/HIF-2 α pathway in the diabetic kidney [J]. Biomed Pharmacother , 2023 , 167 : 115629 .
PACKER M . Mechanisms leading to differential hypoxia-inducible factor signaling in the diabetic kidney modulation by SGLT2 inhibitors and hypoxia mimetics [J]. Am J Kidney Dis , 2021 , 77 ( 2 ): 280 - 286 .
HE J Y , HONG Q , CHEN B X , et al Ginsenoside Rb 1 alleviates diabetic kidney podocyte injury by inhibiting aldose reductase activity [J]. Acta Pharmacol Sin ,2022, 43 ( 2 ): 342 - 353 .
SUN H , LI X , CHEN X , et al . Drp1 activates ROS/HIF-1 α /EZH2 and triggers mitochondrial fragmentation to deteriorate hypercalcemia-associated neuronal injury in mouse model of chronic kidney disease [J]. J Neuroinflammation , 2022 , 19 ( 1 ): 213 .
LIANG S , NAYAK B K , VOGEL K S , et al . TP63 Is significantly upregulated in diabetic kidney [J]. Int J Mol Sci , 2021 , 22 ( 8 ): 4070 .
JIANG Y , XIE F , LV X , et al . Mefunidone ameliorates diabetic kidney disease in STZ and db/db mice [J]. FASEB J , 2021 , 35 ( 1 ): e21198 .
JAHAN H , SIDDIQUI N N , IQBAL S , et al . Indole-linked 1,2,3-triazole derivatives efficiently modulate COX-2 protein and PGE 2 levels in human THP-1 monocytes by suppressing AGE-ROS-NF- κ B nexus [J]. Life Sci , 2022 , 291 : 120282 .
WANG X , YAO B , WANG Y , et al . Macrophage cyclooxygenase-2 protects against development of diabetic nephropathy [J]. Diabetes , 2017 , 66 ( 2 ): 494 - 504 .
FENG X , WANG S , SUN Z , et al . Ferroptosis enhanced diabetic renal tubular injury via HIF-1 α /HO-1 pathway in db/db mice [J]. Front Endocrinol(Lausanne) , 2021 , 12 : 626390 .
DEFRONZO R A , REEVES W B , AWAD A S . Pathophysiology of diabetic kidney disease:Impact of SGLT2 inhibitors [J]. Nat Rev Nephrol , 2021 , 17 ( 5 ): 319 - 334 .
LÖWEN J , GRÖNE E , GRÖNE H J , et al . Herniation of the tuft with outgrowth of vessels through the glomerular entrance in diabetic nephropathy damages the juxtaglomerular apparatus [J]. Am J Physiol Renal Physiol , 2019 , 317 ( 2 ): F399 - F410 .
CHEN M , ZHONG K , TAN J , et al . Baicalein is a novel TLR4-targeting therapeutics agent that inhibits TLR4/HIF-1 α /VEGF signaling pathway in colorectal cancer [J]. Clin Transl Med , 2021 , 11 ( 11 ): e564 .
SUN W X , GAO Y Y , CAO Y , et al . Catalpol prevents glomerular angiogenesis induced by advanced glycation end products via inhibiting galectin-3 [J]. Curr Med Sci , 2023 , 43 ( 4 ): 668 - 678 .
XU Y , KONG X , LI J , et al . Mild hypoxia enhances the expression of HIF and VEGF and triggers the response to injury in rat kidneys [J]. Front Physiol , 2021 , 12 : 690496 .
IKEDA M , IDE T , TADOKORO T , et al . Excessive hypoxia-inducible factor-1 α expression induces cardiac rupture via p53-dependent apoptosis after myocardial infarction [J]. J Am Heart Assoc , 2021 , 10 ( 17 ): e020895 .
YFANTIS A , MYLONIS I , SIMOS G . Direct interaction between mortalin and HIF-1 α at the mitochondria inhibits apoptosis by blocking recruitment of Bax [J]. FEBS J , 2023 , 290 ( 15 ): 3764 - 3780 .
FU M , PENG D , LAN T , et al . Multifunctional regulatory protein connective tissue growth factor(CTGF):A potential therapeutic target for diverse diseases [J]. Acta Pharm Sin B , 2022 , 12 ( 4 ): 1740 - 1760 .
QIAN L , REN S , XU Z , et al . Qianyang Yuyin granule improves renal injury of hypertension by regulating metabolic reprogramming mediated by HIF-1 α /PKM2 positive feedback loop [J]. Front Pharmacol , 2021 , 12 : 667433 .
ARELLANO-BUENDÍA A S , CASTAÑEDA-LARA L G , LOREDO-MENDOZA M L , et al . Effects of allicin on pathophysiological mechanisms during the progression of nephropathy associated to diabetes [J]. Antioxidants(Basel) , 2020 , 9 ( 11 ): 1134 .
LIU L , ZHANG P , BAI M , et al . p53 upregulated by HIF-1 α promotes hypoxia-induced G 2 /M arrest and renal fibrosis in vitro and in vivo [J]. J Mol Cell Biol , 2019 , 11 ( 5 ): 371 - 382 .
ZHAO H , HAN Y , JIANG N , et al . Effects of HIF-1 α on renal fibrosis in cisplatin-induced chronic kidney disease [J]. Clin Sci(Lond) , 2021 , 135 ( 10 ): 1273 - 1288 .
SUN S , NING X , ZHANG Y , et al . Hypoxia-inducible factor-1alpha induces Twist expression in tubular epithelial cells subjected to hypoxia, leading to epithelial-to-mesenchymal transition [J]. Kidney Int , 2009 , 75 ( 12 ): 1278 - 1287 .
何亚萍 , 贾登科 , 陈文英 , 等 . 基于线粒体自噬探讨中医药干预糖尿病肾病的研究进展 [J]. 中医药信息 , 2024 , 41 ( 11 ): 72 - 78 .
HE Y P , JIA D K , CHEN W Y , et al . Research progress on traditional Chinese medicine intervention in diabetic nephropathy based on mitophagy [J]. Inf Tradit Chin Med , 2024 , 41 ( 11 ): 72 - 78 .
CUI K , LIU J , HUANG L , et al . Andrographolide attenuates choroidal neovascularization by inhibiting the HIF-1 α /VEGF signaling pathway [J]. Biochem Biophys Res Commun , 2020 , 530 ( 1 ): 60 - 66 .
LV B , ZHENG K , SUN Y , et al . Network pharmacology experiments show that emodin can exert a protective effect on MCAO rats by regulating Hif-1 α /VEGF-A signaling [J]. ACS Omega , 2022 , 7 ( 26 ): 22577 - 22593 .
XU W L , LIU S , LI N , et al . Quercetin antagonizes glucose fluctuation induced renal injury by inhibiting aerobic glycolysis via HIF-1 α /miR-210/ISCU/FeS pathway [J]. Front Med(Lausanne) , 2021 , 8 : 656086 .
陈水龄 , 亢泽峰 , 褚文丽 , 等 . 姜黄素通过Akt/HIF-1 α /VEGF信号通路在体外抑制脉络膜新生血管的机制 [J]. 国际眼科杂志 , 2022 , 22 ( 4 ): 541 - 548 .
CHEN S L , KANG Z F , CHU W L , et al . Mechanism study of curcumin on inhibiting experimental choroidal neovascularization in vitro by Akt/HIF-1 α /VEGF pathway [J]. Int Eye Sci , 2022 , 22 ( 4 ): 541 - 548 .
候剑 . 黄葵胶囊与雷公藤多苷联合缬沙坦治疗Ⅳ期糖尿病肾病患者的效果 [J]. 河南医学研究 , 2020 , 29 ( 22 ): 4145 - 4147 .
HOU J . Effect of Huangkui capsule and tretinoin polyglucoside combined with valsartan in the treatment of patients with stage Ⅳ diabetic nephropathy [J]. Henan Med Res , 2020 , 29 ( 22 ): 4145 - 4147 .
DONG X G , AN Z M , GUO Y , et al . Effect of triptolide on expression of oxidative carbonyl protein in renal cortex of rats with diabetic nephropathy [J]. J Huazhong Univ Sci Technol Med Sci , 2017 , 37 ( 1 ): 25 - 29 .
于向慧 , 何艳玲 , 杨雨菲 , 等 . 雷公藤多苷通过PI3K/Akt通路对糖尿病肾病大鼠热休克蛋白90及PGC-1 α 表达的影响 [J]. 中国现代医学杂志 , 2021 , 31 ( 22 ): 10 - 16 .
YU X H , HE Y L , YANG Y F , et al . Tripterygium Glycosides tablets affect the levels of heat shock protein 90 and PGC-1 α in rats with diabetic nephropathy through PI3K/Akt pathway [J]. China J Mod Med , 2021 , 31 ( 22 ): 10 - 16 .
李明霞 , 乔海霞 , 王晓玲 , 等 . 雷公藤多苷对高糖诱导人肾小管上皮细胞凋亡及CXCL10/CXCR3轴的影响 [J]. 天津医药 , 2023 , 51 ( 2 ): 139 - 143 .
LI M X , QIAO H X , WANG X L , et al . Effects of tripterygium glycosides on high glucose induced apoptosis of human renal tubular epithelial cells and CXCL10/CXCR3 axis [J]. Tianjin Med J , 2023 , 51 ( 2 ): 139 - 143 .
JIANG S , FAN F , YANG L , et al . Salidroside attenuates high altitude hypobaric hypoxia-induced brain injury in mice via inhibiting NF- κ B/NLRP3 pathway [J]. Eur J Pharmacol , 2022 , 925 : 175015 .
PEI D , TIAN S , BAO Y , et al . Protective effect of salidroside on streptozotocin-induced diabetic nephropathy by inhibiting oxidative stress and inflammation in rats via the Akt/GSK-3 β signalling pathway [J]. Pharm Biol , 2022 , 60 ( 1 ): 1732 - 1738 .
谢瑞燕 , 方雪玲 , HAMZE I , 等 . 红景天苷上调HIF-1 α 减轻高糖诱导的大鼠肾小球内皮细胞损伤 [J]. 中国病理生理杂志 , 2019 , 35 ( 2 ): 237 - 242 .
XIE R Y , FANG X L , HAMZE I , et al . Salidroside attenuates high glucose-induced rat renal glomerular endothelial cell injury via up-regulating HIF-1 α expression [J]. Chin J Pathophysiol , 2019 , 35 ( 2 ): 237 - 242 .
WANG S , ZHAO X , YANG S , et al . Salidroside alleviates high glucose-induced oxidative stress and extracellular matrix accumulation in rat glomerular mesangial cells by the TXNIP-NLRP3 inflammasome pathway [J]. Chem Biol Interact , 2017 , 278 : 48 - 53 .
单娟萍 , 官继超 , 董志超 , 等 . 冬虫夏草通过抗氧化抗炎抑制细胞凋亡改善顺铂肾损伤 [J]. 中国中西医结合肾病杂志 , 2019 , 20 ( 6 ): 474 - 477,565 .
SHAN J P , GUAN J C , DONG Z C , et al . Cordyceps sinensis ameliorates cisplatin-induced nephrotoxicity in mice through inhibition of oxidative stress,inflammation,and apoptosis [J]. Chin J Integr Tradit West Nephrol , 2019 , 20 ( 6 ): 474 - 477,565 .
张隆业 , 金健 , 金吉哲 , 等 . 虫草提取物CS-4对他克莫司所致大鼠胰腺和肾脏损伤的保护 [J]. 中国老年学杂志 , 2019 , 39 ( 2 ): 361 - 367 .
ZHANG L Y , JIN J , JIN J Z , et al . Cordyceps sinensis protects against tacrolimus-induced pancreatic and pe-nal injury [J]. Chin J Gerontol , 2019 , 39 ( 2 ): 361 - 367 .
袁明霞 , 唐荣 , 周巧玲 , 等 . 冬虫夏草对糖尿病肾病大鼠肾组织HIF-1 α 及VEGF表达的影响 [J]. 中南大学学报:医学版 , 2013 , 38 ( 5 ): 448 - 457 .
YUAN M X , TANG R , ZHOU Q L , et al . Effect of Cordyceps sinensi s on expressions of HIF-1 α and VEGF in the kidney of rats with diabetic nephropathy [J]. J Central South Univ: Med Sci , 2013 , 38 ( 5 ): 448 - 457 .
KU C W , HO T J , HUANG C Y , et al . Cordycepin attenuates palmitic acid-Induced inflammation and apoptosis of vascular endothelial cells through mediating PI3K/Akt/eNOS signaling pathway [J]. Am J Chin Med , 2021 , 49 ( 7 ): 1703 - 1722 .
SHAO Y , LV C , WU C , et al . Mir-217 promotes inflammation and fibrosis in high glucose cultured rat glomerular mesangial cells via Sirt1/HIF-1 α signaling pathway [J]. Diabetes Metab Res Rev , 2016 , 32 ( 6 ): 534 - 543 .
DU L , WANG L , WANG B , et al . A novel compound AB38b attenuates oxidative stress and ECM protein accumulation in kidneys of diabetic mice through modulation of Keap1/Nrf2 signaling [J]. Acta Pharmacol Sin , 2020 , 41 ( 3 ): 358 - 372 .
宋玮 , 刘国玲 , 田华 , 等 . 白皮杉醇对糖尿病肾病大鼠肾纤维化及HO-1、HIF-1 α 蛋白表达的影响 [J]. 营养学报 , 2021 , 43 ( 1 ): 86 - 91 .
SONG W , LIU G Y , TIAN H , et al . Effects of piceatannol on renal fibrosis and HO-1 and HIF-1 a expressions in diabetic nephropathy rats [J]. Acta Nutr Sin , 2021 , 43 ( 1 ): 86 - 91 .
陈伟 , 田鲁 , 李易 , 等 . 苦瓜总皂苷对2型糖尿病肾病大鼠肾脏组织中HIF-1 α 和VEGF表达的作用研究 [J]. 环球中医药 , 2016 , 9 ( 6 ): 659 - 663 .
CHEN W , TIAN L , LI Y , et al . Effects of momordica total saponins to HIF-1 α and VEGF expression in kidney tissue of type 2 diabetic nephropathy rats [J]. Global Tradit Chin Med , 2016 , 9 ( 6 ): 659 - 663 .
CHEN J , OU Z , GAO T , et al . Ginkgolide B alleviates oxidative stress and ferroptosis by inhibiting GPX4 ubiquitination to improve diabetic nephropathy [J]. Biomed Pharmacother , 2022 , 156 : 113953 .
WILLSON J A , ARIENTI S , SADIKU P , et al . Neutrophil HIF-1 α stabilization is augmented by mitochondrial ROS produced via the glycerol 3-phosphat e shuttle [J]. Blood , 2022 , 139 ( 2 ): 281 - 286 .
WANG Y , CAO Z , WEI Q , et al . VH298-loaded extracellular vesicles released from gelatin methacryloyl hydrogel facilitate diabetic wound healing by HIF-1 α -mediated enhancement of angiogenesis [J]. Acta Biomater , 2022 , 147 : 342 - 355 .
FU Z J , WANG Z Y , XU L , et al . HIF-1 α -BNIP3-mediated mitophagy in tubular cells protects against renal ischemia/reperfusion injury [J]. Redox Biol , 2020 , 36 : 101671 .
XU B , ZHENG J , TIAN X , et al . Protective mechanism of traditional Chinese medicine Guizhi Fuling pills against carbon tetrachloride-induced kidney damage is through inhibiting oxidative stress, inflammation and regulating the intestinal flora [J]. Phytomedicine , 2022 , 101 : 154129 .
YANG Y Q , TAN H B , ZHANG X Y , et al . The Chinese medicine Fufang Zhenzhu Tiaozhi capsule protects against renal injury and inflammation in mice with diabetic kidney disease [J]. J Ethnopharmacol , 2022 , 292 : 115165 .
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