Message Board

Respected readers, authors and reviewers, you can add comments to this page on any questions about the contribution, review,        editing and publication of this journal. We will give you an answer as soon as possible. Thank you for your support!

Name
E-mail
Phone
Title
Content
Verification Code
Volume 41 Issue 10
Oct.  2023
Turn off MathJax
Article Contents

SHI Xiaofei, CHEN Yi, XIANG Kefa, ZHANG Huimin, GAO Yue, LIU Xia. Research progress on innovative drugs for diabetic nephropathy with potential anti-inflammatory targets[J]. Journal of Pharmaceutical Practice and Service, 2023, 41(10): 581-585, 628. doi: 10.12206/j.issn.2097-2024.202109068
Citation: SHI Xiaofei, CHEN Yi, XIANG Kefa, ZHANG Huimin, GAO Yue, LIU Xia. Research progress on innovative drugs for diabetic nephropathy with potential anti-inflammatory targets[J]. Journal of Pharmaceutical Practice and Service, 2023, 41(10): 581-585, 628. doi: 10.12206/j.issn.2097-2024.202109068

Research progress on innovative drugs for diabetic nephropathy with potential anti-inflammatory targets

doi: 10.12206/j.issn.2097-2024.202109068
  • Received Date: 2021-09-13
  • Rev Recd Date: 2022-04-20
  • Available Online: 2023-10-23
  • Publish Date: 2023-10-25
  • Diabetic nephropathy (DN) is a common microvascular complication of type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM), which is also the main cause of chronic kidney disease (CKD) and end-stage renal disease (ESRD). However, the treatment methods are limited at present. More and more evidences have indicated that inflammatory response is involved in the pathogenesis and progression of DN. Several anti-inflammatory strategies that target specific inflammatory mediators (transcription factors, pro-inflammatory cytokines, chemokines, adhesion molecules) and intracellular signaling pathways have shown benefits in the DN rodent model. The mechanisms related to inflammation in the development and progression of DN were summarized and new strategies to prevent or treat DN based on inflammation were briefly discussed in this review.
  • [1] International Diabetic Federation. IDF Diabetes Atlas 2021[EB/OL]. (2021-11-08) [2022-04-16]. http://www.diabetesatlas.org/atlas/tenth-edition
    [2] ZHANG P, ZHU L H, CAI J J, et al. Association of inpatient use of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers with mortality among patients with hypertension hospitalized with COVID-19[J]. Circ Res,2020,126(12):1671-1681. doi:  10.1161/CIRCRESAHA.120.317134
    [3] CATALÁ-LÓPEZ F, MACÍAS SAINT-GERONS D, DE LA FUENTE HONRUBIA C, et al. Risks of dual blockade of the renin-angiotensin system compared with monotherapy: a systematic review and cumulative meta-analysis of randomized trials and observational studies[J]. Rev Esp Salud Publica,2014,88(1):37-65. doi:  10.4321/S1135-57272014000100004
    [4] NAVARRO-GONZÁLEZ J F, MORA-FERNÁNDEZ C, MUROS DE FUENTES M, et al. Inflammatory molecules and pathways in the pathogenesis of diabetic nephropathy[J]. Nat Rev Nephrol,2011,7(6):327-340. doi:  10.1038/nrneph.2011.51
    [5] LUSTER A D. Chemokines: chemotactic cytokines that mediate inflammation[J]. N Engl J Med,1998,338(7):436-445. doi:  10.1056/NEJM199802123380706
    [6] MOSER B, LOETSCHER P. Lymphocyte traffic control by chemokines[J]. Nat Immunol,2001,2(2):123-128. doi:  10.1038/84219
    [7] SHI Y F, WANG Y, LI Q, et al. Immunoregulatory mechanisms of mesenchymal stem and stromal cells in inflammatory diseases[J]. Nat Rev Nephrol,2018,14(8):493-507. doi:  10.1038/s41581-018-0023-5
    [8] FADINI G P, BONORA B M, CAPPELLARI R, et al. Acute effects of linagliptin on progenitor cells, monocyte phenotypes, and soluble mediators in type 2 diabetes[J]. J Clin Endocrinol Metab,2016,101(2):748-756. doi:  10.1210/jc.2015-3716
    [9] GIUNTI S, BARUTTA F, PERIN P C, et al. Targeting the MCP-1/CCR2 System in diabetic kidney disease[J]. Curr Vasc Pharmacol,2010,8(6):849-860. doi:  10.2174/157016110793563816
    [10] PEREZ-GOMEZ M V, SANCHEZ-NIÑO M D, SANZ A B, et al. Targeting inflammation in diabetic kidney disease: early clinical trials[J]. Expert Opin Investig Drugs,2016,25(9):1045-1058. doi:  10.1080/13543784.2016.1196184
    [11] MENNE J, EULBERG D, BEYER D, et al. C-C motif-ligand 2 inhibition with emapticap pegol (NOX-E36) in type 2 diabetic patients with albuminuria[J]. Nephrol Dial Transplant,2017,32(2):307-315.
    [12] LI H Y, LIN H G, NIEN F J, et al. Serum vascular adhesion protein-1 predicts end-stage renal disease in patients with type 2 diabetes[J]. PLoS One,2016,11(2):e0147981. doi:  10.1371/journal.pone.0147981
    [13] QIAN Y, LI S, YE S, et al. Renoprotective effect of rosiglitazone through the suppression of renal intercellular adhesion molecule-1 expression in streptozotocin-induced diabetic rats[J]. J Endocrinol Investig,2008,31(12):1069-1074. doi:  10.1007/BF03345654
    [14] KOSUGI T, NAKAYAMA T, HEINIG M, et al. Effect of lowering uric acid on renal disease in the type 2 diabetic db/db mice[J]. Am J Physiol Renal Physiol,2009,297(2):F481-F488. doi:  10.1152/ajprenal.00092.2009
    [15] LIU J J, YEOH L Y, SUM C F, et al. Vascular cell adhesion molecule-1, but not intercellular adhesion molecule-1, is associated with diabetic kidney disease in Asians with type 2 diabetes[J]. J Diabetes Complications,2015,29(5):707-712. doi:  10.1016/j.jdiacomp.2015.02.011
    [16] RUBIO-GUERRA A F, VARGAS-ROBLES H, LOZANO NUEVO J J, et al. Correlation between circulating adhesion molecule levels and albuminuria in type-2 diabetic hypertensive patients[J]. Kidney Blood Press Res,2009,32(2):106-109. doi:  10.1159/000210554
    [17] SALMI M, KALIMO K, JALKANEN S. Induction and function of vascular adhesion protein-1 at sites of inflammation[J]. J Exp Med,1993,178(6):2255-2260. doi:  10.1084/jem.178.6.2255
    [18] SALMI M, JALKANEN S. Vascular adhesion protein-1: a cell surface amine oxidase in translation[J]. Antioxid Redox Signal,2019,30(3):314-332. doi:  10.1089/ars.2017.7418
    [19] DE ZEEUW D, RENFURM R W, BAKRIS G, et al. Efficacy of a novel inhibitor of vascular adhesion protein-1 in reducing albuminuria in patients with diabetic kidney disease (ALBUM): a randomised, placebo-controlled, phase 2 trial[J]. Lancet Diabetes Endocrinol,2018,6(12):925-933. doi:  10.1016/S2213-8587(18)30289-4
    [20] SANCHEZ A P, SHARMA K. Transcription factors in the pathogenesis of diabetic nephropathy[J]. Expert Rev Mol Med,2009,11:e13. doi:  10.1017/S1462399409001057
    [21] MEZZANO S, AROS C, DROGUETT A, et al. NF-kappaB activation and overexpression of regulated genes in human diabetic nephropathy[J]. Nephrol Dial Transplant,2004,19(10):2505-2512. doi:  10.1093/ndt/gfh207
    [22] YANG B M, HODGKINSON A, OATES P J, et al. High glucose induction of DNA-binding activity of the transcription factor NFkappaB in patients with diabetic nephropathy[J]. Biochim Biophys Acta,2008,1782(5):295-302. doi:  10.1016/j.bbadis.2008.01.009
    [23] OHGA S, SHIKATA K, YOZAI K, et al. Thiazolidinedione ameliorates renal injury in experimental diabetic rats through anti-inflammatory effects mediated by inhibition of NF-kappaB activation[J]. Am J Physiol Renal Physiol,2007,292(4):F1141-F1150. doi:  10.1152/ajprenal.00288.2005
    [24] ZHANG Z, YUAN W, SUN L, et al. 1, 25-Dihydroxyvitamin D3 targeting of NF-kappaB suppresses high glucose-induced MCP-1 expression in mesangial cells[J]. Kidney Int,2007,72(2):193-201. doi:  10.1038/sj.ki.5002296
    [25] ZHU L P, HAN J K, YUAN R R, et al. Berberine ameliorates diabetic nephropathy by inhibiting TLR4/NF-κB pathway[J]. Biol Res,2018,51(1):9. doi:  10.1186/s40659-018-0157-8
    [26] SIERRA-MONDRAGON E, MOLINA-JIJON E, NAMORADO-TONIX C, et al. All-trans retinoic acid ameliorates inflammatory response mediated by TLR4/NF-κB during initiation of diabetic nephropathy[J]. J Nutr Biochem,2018,60:47-60. doi:  10.1016/j.jnutbio.2018.06.002
    [27] ZHANG S, WANG W D, MA J, et al. Coumarin glycosides from Hydrangea paniculata slow down the progression of diabetic nephropathy by targeting Nrf2 anti-oxidation and smad2/3-mediated profibrosis[J]. Phytomedicine,2019,57:385-395. doi:  10.1016/j.phymed.2018.12.045
    [28] JIANG T, HUANG Z P, LIN Y F, et al. The protective role of Nrf2 in streptozotocin-induced diabetic nephropathy[J]. Diabetes,2010,59(4):850-860. doi:  10.2337/db09-1342
    [29] PERGOLA P E, RASKIN P, TOTO R D, et al. Bardoxolone methyl and kidney function in CKD with type 2 diabetes[J]. N Engl J Med,2011,365(4):327-336. doi:  10.1056/NEJMoa1105351
    [30] DE ZEEUW D, AKIZAWA T, AUDHYA P, et al. Bardoxolone methyl in type 2 diabetes and stage 4 chronic kidney disease[J]. N Engl J Med,2013,369(26):2492-2503. doi:  10.1056/NEJMoa1306033
    [31] MARRERO M B, BANES-BERCELI A K, STERN D M, et al. Role of the JAK/STAT signaling pathway in diabetic nephropathy[J]. Am J Physiol Renal Physiol,2006,290(4):F762-F768. doi:  10.1152/ajprenal.00181.2005
    [32] BERTHIER C C, ZHANG H Y, SCHIN M, et al. Enhanced expression of Janus kinase-signal transducer and activator of transcription pathway members in human diabetic nephropathy[J]. Diabetes,2009,58(2):469-477. doi:  10.2337/db08-1328
    [33] ZHANG H Y, NAIR V, SAHA J, et al. Podocyte-specific JAK2 overexpression worsens diabetic kidney disease in mice[J]. Kidney Int,2017,92(4):909-921. doi:  10.1016/j.kint.2017.03.027
    [34] TUTTLE K R, BROSIUS F C, ADLER S G, et al. JAK1/JAK2 inhibition by baricitinib in diabetic kidney disease: results from a Phase 2 randomized controlled clinical trial[J]. Nephrol Dial Transplant,2018,33(11):1950-1959. doi:  10.1093/ndt/gfx377
    [35] PANCHAPAKESAN U, PEGG K, GROSS S, et al. Effects of SGLT2 inhibition in human kidney proximal tubular cells: renoprotection in diabetic nephropathy? PLoS One,2013,8(2):e54442. doi:  10.1371/journal.pone.0054442
    [36] SCHEEN A J. Evaluating SGLT2 inhibitors for type 2 diabetes: pharmacokinetic and toxicological considerations[J]. Expert Opin Drug Metab Toxicol,2014,10(5):647-663. doi:  10.1517/17425255.2014.873788
    [37] DEL P S. Role of glucotoxicity and lipotoxicity in the pathophysiology of Type 2 diabetes mellitus and emerging treatment strategies[J]. Diabet Med,2009,26(12):1185-1192. doi:  10.1111/j.1464-5491.2009.02847.x
    [38] MEROVCI A, MARI A, SOLIS C, et al. Dapagliflozin lowers plasma glucose concentration and improves β-cell function[J]. J Clin Endocrinol Metab,2015,100(5):1927-1932. doi:  10.1210/jc.2014-3472
    [39] VALLON V, GERASIMOVA M, ROSE M A, et al. SGLT2 inhibitor empagliflozin reduces renal growth and albuminuria in proportion to hyperglycemia and prevents glomerular hyperfiltration in diabetic Akita mice[J]. Am J Physiol Renal Physiol,2014,306(2):F194-F204. doi:  10.1152/ajprenal.00520.2013
    [40] TANG L, WU Y Y, TIAN M, et al. Dapagliflozin slows the progression of the renal and liver fibrosis associated with type 2 diabetes[J]. Am J Physiol Endocrinol Metab,2017,313(5):E563-E576. doi:  10.1152/ajpendo.00086.2017
    [41] DEKKERS C C J, PETRYKIV S, LAVERMAN G D, et al. Effects of the SGLT-2 inhibitor dapagliflozin on glomerular and tubular injury markers[J]. Diabetes Obes Metab,2018,20(8):1988-1993. doi:  10.1111/dom.13301
    [42] GENTILELLA R, PECHTNER V, CORCOS A, et al. Glucagon-like peptide-1 receptor agonists in type 2 diabetes treatment: are they all the same? [J]. Diabetes Metab Res Rev, 2019, 35(1): e3070.
    [43] MADSBAD S. Review of head-to-head comparisons of glucagon-like peptide-1 receptor agonists[J]. Diabetes Obes Metab,2016,18(4):317-332. doi:  10.1111/dom.12596
    [44] PHILIS-TSIMIKAS A, WYSHAM C H, HARDY E, et al. Efficacy and tolerability of exenatide once weekly over 7 years in patients with type 2 diabetes: an open-label extension of the DURATION-1 study[J]. J Diabetes Complications,2019,33(3):223-230. doi:  10.1016/j.jdiacomp.2018.11.012
    [45] SBIDIAN E, CHAIMANI A, GARCIA-DOVAL I, et al. Systemic pharmacological treatments for chronic plaque psoriasis: a network meta-analysis[J]. Cochrane Database Syst Rev,2017,12(12):CD011535.
    [46] KODERA R, SHIKATA K, KATAOKA H U, et al. Glucagon-like peptide-1 receptor agonist ameliorates renal injury through its anti-inflammatory action without lowering blood glucose level in a rat model of type 1 diabetes[J]. Diabetologia,2011,54(4):965-978. doi:  10.1007/s00125-010-2028-x
    [47] PARK C W, KIM H W, KO S H, et al. Long-term treatment of glucagon-like peptide-1 analog exendin-4 ameliorates diabetic nephropathy through improving metabolic anomalies in db/db mice[J]. J Am Soc Nephrol,2007,18(4):1227-1238. doi:  10.1681/ASN.2006070778
    [48] BALAKUMAR P, KADIAN S, MAHADEVAN N. Are PPAR alpha agonists a rational therapeutic strategy for preventing abnormalities of the diabetic kidney? [J]. Pharmacol Res, 2012, 65(4): 430-436.
    [49] DAL CANTO E, CERIELLO A, RYDÉN L, et al. Diabetes as a cardiovascular risk factor: an overview of global trends of macro and micro vascular complications[J]. Eur J Prev Cardiol,2019,26(2_suppl):25-32. doi:  10.1177/2047487319878371
  • 加载中
通讯作者: 陈斌, bchen63@163.com
  • 1. 

    沈阳化工大学材料科学与工程学院 沈阳 110142

  1. 本站搜索
  2. 百度学术搜索
  3. 万方数据库搜索
  4. CNKI搜索

Article Metrics

Article views(2264) PDF downloads(42) Cited by()

Related
Proportional views

Research progress on innovative drugs for diabetic nephropathy with potential anti-inflammatory targets

doi: 10.12206/j.issn.2097-2024.202109068

Abstract: Diabetic nephropathy (DN) is a common microvascular complication of type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM), which is also the main cause of chronic kidney disease (CKD) and end-stage renal disease (ESRD). However, the treatment methods are limited at present. More and more evidences have indicated that inflammatory response is involved in the pathogenesis and progression of DN. Several anti-inflammatory strategies that target specific inflammatory mediators (transcription factors, pro-inflammatory cytokines, chemokines, adhesion molecules) and intracellular signaling pathways have shown benefits in the DN rodent model. The mechanisms related to inflammation in the development and progression of DN were summarized and new strategies to prevent or treat DN based on inflammation were briefly discussed in this review.

SHI Xiaofei, CHEN Yi, XIANG Kefa, ZHANG Huimin, GAO Yue, LIU Xia. Research progress on innovative drugs for diabetic nephropathy with potential anti-inflammatory targets[J]. Journal of Pharmaceutical Practice and Service, 2023, 41(10): 581-585, 628. doi: 10.12206/j.issn.2097-2024.202109068
Citation: SHI Xiaofei, CHEN Yi, XIANG Kefa, ZHANG Huimin, GAO Yue, LIU Xia. Research progress on innovative drugs for diabetic nephropathy with potential anti-inflammatory targets[J]. Journal of Pharmaceutical Practice and Service, 2023, 41(10): 581-585, 628. doi: 10.12206/j.issn.2097-2024.202109068
    • 糖尿病已经成为世界范围内的公共卫生问题。根据国际糖尿病联盟(IDF)2021年最新数据,糖尿病已成为影响全球5.37亿人的健康负担,预计到2045年,这一数字将增加到7.83亿[1]。糖尿病肾病(DN)是糖尿病最重要的微血管并发症之一,是指由糖尿病所致的慢性肾脏疾病。目前,DN的标准药物治疗方法是肾素血管紧张素醛固酮系统(RAS)的抑制剂,包括血管紧张素转化酶抑制剂(ACEI)和血管紧张素II受体阻滞剂(ARB)[2]。ACEI和ARB在减缓DN的进展中发挥了重要作用,它们可以降低尿蛋白水平,降低血压,减缓DN进展。但是,长期使用RAS抑制剂会带来很多副作用,如高钾血症、低血压、降低肾小球滤过率和肾血流量[3]。因此,迫切需要其他可用于阻止DN进展的药物。

      DN的发病机制复杂,病因和发病机制目前尚不明确,以往的研究成果提示代谢紊乱、炎性反应机制、氧化应激、血流动力学改变、细胞因子、遗传因素及自噬等多种因素导致DN的发生与发展。近期研究表明,炎症似乎是DN的主要发病机制,调节炎症可作为治疗DN新的方向和热点。炎症与DN的发生和发展之间的关系涉及复杂的分子网络和过程,主要是促炎途径增强。其中,比较重要的促炎分子和途径包括:趋化因子,如CCL2、CX3CL1和CCL5;黏附分子,如细胞间黏附分子1(ICAM1),血管细胞黏附蛋白1(VCAM-1)和血管黏附蛋白1(VAP-1);转录因子,如核因子κB(NF-κB),核因子红血球2相关因子2(Nrf2);Janus激酶(JAK)信号转导和转录激活因子(STAT)通路。因此,本综述重点阐述这些促炎分子在DN中的作用和相应靶向药物的研究进展[4],并简单介绍对DN具有抗炎作用的糖尿病新型药物。

    • 趋化因子及其受体在细胞迁移的募集中起关键作用。根据它们的N端半胱氨酸基序,可将它们大致分为4个亚家族(CC、C、CXC和CX3C家族)[5]。趋化因子根据功能可被定义为“稳态”趋化因子和“炎症”趋化因子。稳态趋化因子是组成型分泌的,主要参与淋巴细胞的运输。炎症趋化因子与促炎机制相关,诱导白细胞募集到受损组织[6]。趋化因子与DN密切相关。当暴露于DN的炎性环境中,间充质干细胞可以通过释放趋化因子来调节局部和全身性先天性和适应性免疫反应[7]

      最重要的CC趋化因子家族是CCL2,也称为巨噬细胞趋化因子1(MCP-1),它对细胞迁移、增殖和分化具有直接的信号传导作用。同时,CCL2还可以反映DN中肾小管损伤和肾脏炎症水平[8]。CCL2和趋化因子受体2(CCR2)结合,驱动T细胞和巨噬细胞向肾脏的募集,促进DN发生与发展[9],抑制CCR2-CCL2轴可以改善该疾病,提示抑制CCR2-CCL2轴可作为肾脏炎性疾病治疗的新策略。CCL2抑制剂丹参聚乙二醇似乎是治疗DN的最有前途的抗炎药物[10]。在II期临床试验中,丹参聚乙二醇可以改善尿白蛋白肌酐比(UACR)和糖化血红蛋白(HbA1c)。重要的是,在停止治疗的4周和8周后,其对蛋白尿和血糖控制的有益作用仍然保持,表明阻断CCL2-CCR2信号具有持续的益处[11]

    • 内皮黏附分子ICAM1、VCAM-1和VAP-1的表达在DN患者中明显增加,并且与疾病严重程度关系紧密[12]。由于这些分子在白细胞与内皮的黏附中起着重要作用,抑制这些分子可能会干扰白细胞的转运,从而减轻DN的炎症。

      ICAM1是一种细胞表面糖蛋白,在免疫系统的内皮细胞和白细胞中表达。有实验发现,与非糖尿病大鼠相比,链脲佐菌素(STZ)诱导的大鼠血清和尿中ICAM1水平升高,且ICAM1的升高与尿白蛋白排泄率的升高相平行[13]。此外,还有证据表明,ICAM1在T2DM db/db小鼠的肾小球和肾小管上皮细胞中也呈现过表达[14],其机制可能是在患有高血糖症的糖尿病患者中,细胞核中ICAM1基因的转录增加,内皮细胞表面ICAM1基因的表达上调。ICAM1与LFA-1的结合活性增加,血液中更多的淋巴细胞转移到肾小球和肾单位的肾小管周围毛细血管中,从而发生肾小球和肾小管的损伤,引起尿液中蛋白质排泄率的增加。

      VCAM1也称CD106,是在多种病理条件下(包括动脉粥样硬化和DN)活化的内皮中表达的跨膜糖蛋白。VCAM1与α4β1整合素结合,后者在淋巴细胞、单核细胞和嗜酸性粒细胞上表达。随着血清中VCAM1水平的升高,肾脏滤过功能下降,尿白蛋白排泄水平也逐渐升高[15]。有实验发现患有2型糖尿病的患者血清中VCAM-1的水平显著升高,且与蛋白尿的程度密切相关[16]。这一发现也在其他2型糖尿病患者得到证实,其中VCAM-1的基线水平不仅与蛋白尿相关,而且与死亡风险增加也相关[15]

      炎症还可以诱导VAP-1的过表达[17]。除了促进内皮细胞与白细胞之间的相互作用外,VAP-1还可以触发其他内皮黏附分子的合成,如ICAM-1和E-选择素,并通过过氧化氢的生成激活炎症信号通路,包括MAPK和NF-κB通路[18]。ALBUM的II期临床试验采用随机、双盲、安慰剂对照的方法,将125名参与者被随机分配接受VAP-1抑制剂ASP8232(n=64)或安慰剂(n=61),给药12周。结果发现,ASP8232对DN有良好的疗效,具体表现为DN患者的蛋白尿减少、肾小球滤过率(GFR)下降减缓[19]

    • 由于转录因子可以激活炎症通路,因此抑制转录因子治疗DN是另一种新的抗炎方法。几种转录因子,例如上游刺激因子1、2,激活蛋白1,NF-κB,cAMP-反应元件结合蛋白,活化的T细胞核因子和刺激蛋白1可在高血糖环境中被激活。这些转录因子与炎症和细胞外基质产量有关[20]。在这些转录因子中,NF-κB在DN的发病机理中最为重要。在DN疾病中,蛋白尿本身是NF-κB的重要激活剂,并且是肾小管细胞重要的炎症刺激[21]。NF-κB结合在DN发病机制中起关键作用的几个基因的启动子区域,例如编码TGF-β1,AKR1B1(醛酮还原酶家族1、成员B1),CCL2和ICAM1[22]。噻唑烷二酮类[23],1,25-二羟基维生素D3[24],小檗碱[25]和全反式维甲酸[26]等多种药物抑制NF-κB活化,可改善DN,提示NF-κB可作为DN的治疗靶标。

      Nrf2可调节谷胱甘肽S-转移酶、谷胱甘肽过氧化物酶和血红素加氧酶-1等多种抗氧化酶的表达。在STZ建立了1型糖尿病大鼠模型中,给予绣球香豆素苷治疗3个月发现,糖尿病大鼠的血尿素氮和血清肌酐含量以及尿白蛋白排泄明显减少,而肌酐清除率明显增加,同时,显著下降的ROS产生,增加Nrf2的mRNA水平[27]。在STZ诱导的DN小鼠中,Nrf2-/-小鼠ROS的产生增加,且UACR明显高于野生型小鼠[28]。说明Nrf2可以通过抗氧化作用保护STZ所致的肾损伤。

      甲基巴多索隆是一种有效的NF-κB抑制剂和Nrf2激活剂,是一种抗氧化的炎症调节剂。有关于甲基巴多索隆II期临床试验显示,在治疗DN过程中,与安慰剂组相比,治疗组在52周时持续增加GFR,且具有良好的效果[29]。然而,在III期临床试验中,给予2型糖尿病患者和4期慢性肾脏疾病的患者甲基巴多索隆治疗时,患者的GFR估计值显著增加,但由于心血管原因死亡的出现,该研究被迫终止了[30]。值得思考的是,是否可以通过调节剂量、对甲基巴多索隆化学结构进行改造,从而获得安全可靠的药物?

    • JAK-STAT通路的激活与DN的发病机制有关[31]。有研究发现,DN患者的肾小球和肾小管间质区域中的多种JAK和STAT同工型(JAK1、JAK2、JAK3、STAT1、STAT3),在表达水平上均高于对照组。在早期DN和肾功能正常的患者中,各种JAK和STAT同工型均出现强烈的肾小球过度表达。然而,在进行性DN且肾功能下降的患者中,肾小球JAK和STAT mRNA表达大多恢复正常,而肾小管间质表达显著增加。同时,与无肾脏疾病的患者相比,进行性肾脏疾病患者的近端肾小管细胞中JAK2蛋白的表达较高,甚至与少数患有其他肾小球疾病的患者相比也是如此。JAK2蛋白还在肾小球细胞,包括足细胞中表达。这种表达方式表明,DN中JAK2表达的变化反映了内在肾细胞而非浸润性炎症细胞的变化[32]。研究发现,足细胞JAK2的过表达对正常小鼠中几乎没有变化,但是在糖尿病小鼠中,JAK2导致DN的肾小球功能和病理特征显著增加,包括蛋白尿、肾小球系膜扩张、足细胞密度降低、肾小球硬化和肾小球基底膜增厚。通过口服JAK1和JAK2抑制剂治疗2周,这些功能却得到了显著改善[33]

      对T2DM和eGFR25~70 ml/(min·1.73 m)患者进行II期临床试验结果表明,即使在DN疾病的晚期,口服JAK1和JAK2的选择性抑制剂巴利替尼,在24周的研究期间减少了患者的蛋白尿,表明JAK1和JAK2抑制剂在治疗DN方面具有潜在的治疗作用[34]。此外,尿CXCL10和CCL2以及TNFR1和TNFR2等炎症生物标志物的水平也随着巴利替尼的治疗而降低,提示巴利替尼通过抗炎作用对肾具有保护作用。

      虽然临床前期和早期临床数据令人鼓舞,但巴利替尼或其他JAK抑制剂是否会在肾功能丧失和ESRD的发展以及其他并发症方面对DN的进展显示出积极的影响还尚不确定。另外,长期服用JAK抑制剂治疗DN是否安全?因为这些试剂被开发用于治疗自身免疫性疾病以及骨髓增生异常综合征,如果长期治疗可能致使许多DN患者贫血症状加重。

    • 钠/葡萄糖协同转运蛋白2(SGLT2)抑制剂为新型的口服降糖药,达格列净、卡格列净和恩格列净是SGLT2抑制剂的药物,可用于降低高血糖症和帮助控制血糖。它们还可用于治疗轻度肾功能不全,并具有多种有益作用,例如降低体质量和降低血压[35]。SGLT2抑制剂的药动学特性有优异的口服生物利用度和相当长的消除半衰期,允许每天一次给药,较短的蓄积指数,无活性代谢产物,肾脏排泄不受限制[36]

      此外,SGLT2抑制剂可以改善β细胞功能,可能是减少葡萄糖毒性的作用所致[37-38]。有实验研究表明SGLT2抑制剂对肾脏组织也有抗炎作用。例如,恩格列净可降低糖尿病秋田小鼠IL-6、CCL2和NF-κB的肾表达[39]。同样,在培养的肾小管细胞中,恩格列净可降低了高糖诱导的TLR4、NF-κB和IL-6的过表达[35]。达格列净不仅减少尿蛋白的产生,而且还能降低db/db小鼠肾组织中炎症(CCL2和NF-κB)和氧化应激(NOX2和NOX4)的标志物水平[40]。有交叉临床试验,采用前瞻性、随机、双盲、安慰剂对照的方法,将33名2型糖尿病患者进行分组,评估SGLT2 抑制剂达格列净对肾小球标志物(IgG-IgG4和IgG-白蛋白)、肾小管标志物(尿液KIM-1、NGAL和LFABP)和炎症标志物的影响(尿MCP-1和IL-6),以便更深入地了解肾脏保护作用。经过达格列净治疗6周后显示,患者的尿中蛋白降低。同时,与安慰剂相比,达格列净使IgG和IgG4的清除率分别降低了28.4%和34.6%,使尿KIM-1排泄减少22.6%,但没有改变尿中NGAL的排泄量,使尿IL-6排泄减少23.5%,尿MCP-1排泄减少14.1%。结果提示,SGLT2抑制剂达格列净可能通过抗炎的作用保护DN患者的肾脏[41]

    • 胰高血糖素样肽1(GLP-1)受体激动剂(GLP-1RAs)是一种抗糖尿病药。迄今为止,已经批准上述6种GLP-1RA用于治疗2型糖尿病患者,并且所有这些药物均通过皮下注射给药[42]。基于药动学特征,可将GLP1受体激动剂的药物分为两个不同的组:短效激动剂(每日两次口服:艾塞那肽,利西拉肽)和长效激动剂(每周一次注射:杜拉鲁肽、利拉鲁肽、司马鲁肽、阿必鲁肽)[42-43]

      有分析表明,在降低糖化血红蛋白方面,长效激动剂比短效激动剂更为成功[44-45]。在STZ诱导的DN大鼠中,GLP1受体激动剂艾塞那肽的肾保护作用与其降糖作用无关[46]。在该模型中,给予艾塞那肽可降低细胞间黏附分子在肾脏组织中的表达和抑制NF-κB的激活。同样,用艾塞那肽治疗降低了糖尿病db/db小鼠肾小球浸润炎症细胞的水平。艾塞那肽能够改善DN与转录因子过氧化物酶体增殖物激活受体-α(PPARα)的肾脏表达增加有关。这些实验都解释了GLP1受体激动剂的抗炎作用,因为PPARα调节参与了炎症的基因的表达(例如编码NF-κB、PAI-1和ICAM-1的基因)[47-48]

    • 预计在未来几十年中,随着肥胖人口数量的增加,全球糖尿病的负担将急剧增加。DN是糖尿病最重要的微血管并发症之一,它会大大增加心血管疾病的发病率和病死率[49]。目前,预防或减缓DN进展的疗法有广泛应用,然而这些疗法提供的保护还远远不够。我们还需要寻找治疗DN的新靶标和策略。针对DN的新疗法集中于调节炎症通路,控制DN的功能和结构异常。主要包括针对一些转录因子、促炎性细胞因子、趋化因子及其受体、黏附分子、JAK/STAT 通路以及Nrf2调节的抗氧化的化合物在临床前研究中显示出显著的功效。一些初期的临床试验(例如,巴利替尼、甲基巴多索隆)也在DN患者中取得了可喜的结果。同时,SGLT2抑制剂和GLP-1受体激动剂的临床试验也对DN患者产生了有益的影响。这无疑为通过调节炎症治疗DN的动物实验和临床试验带来理论指导和希冀。因此,在未来针对特定分子标记的抗炎目标可能是DN的有前途的治疗策略。

Reference (49)

Catalog

    /

    DownLoad:  Full-Size Img  PowerPoint
    Return
    Return