Skip to main content
NCBI home page
Journal of Central South University Medical Sciences logoLink to Journal of Central South University Medical Sciences
. 2021 Dec 28;46(12):1403–1408. [Article in Chinese] doi: 10.11817/j.issn.1672-7347.2021.210199

氧化应激介导糖尿病肾病足细胞损伤机制的研究进展

Research advance in the mechanism for oxidative stress-induced podocyte injury in diabetic kidney disease

AO Liyun 1,2, XIE Yanyun 1,✉
Editor: 傅 希文
PMCID: PMC10930572  PMID: 35232911

Abstract

Diabetic kidney disease (DKD) is one of the serious microvascular complications of diabetes mellitus (DM), and it is also the leading cause for the end-stage kidney disease (ESKD), but the clinical treatment for it is limited at present. The pathogenesis of DKD is complex. Many studies have shown that podocyte injury is the core event of DKD, and oxidative stress is closely related to podocyte injury in DKD. Oxidative stress mediates podocyte apoptosis and slit diaphragm damage in DKD through various pathways. The antioxidant drugs can slow down the progression of DKD through reducing podocyte injury and are expected to enter clinical trials. The research status of antioxidant drugs is very important, which will provide new strategies for the clinical treatment of DKD.

Keywords: diabetic kidney disease, podocyte injury, oxidative stress

糖尿病肾病(diabetic kidney disease，DKD)是继发于糖尿病(diabetes mellitus，DM)的肾特殊病理结构和功能改变的疾病，已成为全球终末期肾病(end-stage kidney disease，ESKD)的首要病因[1]。临床上30%~50%的DM患者发展为DKD，且有1/3的患者最后发展为ESKD[1]。DKD临床表现为蛋白尿、高血压和进行性肾功能减退。治疗方式以控制血糖、控制血压、抑制肾素-血管紧张素系统和降低心血管风险为主，然而其临床治疗效果仍不甚满意。因此，探讨DKD的主要发病机制对发掘更有效的治疗方式尤为重要。

近几年研究[2]表明足细胞损伤是DKD发展的核心环节。足细胞也称为肾小球脏层上皮细胞，呈高度分化，与肾小球毛细血管内皮细胞、基底膜一同构成肾小球滤过膜，足细胞损伤与蛋白尿的产生密切相关[2]。足细胞损伤涉及多种发病机制，包括氧化应激[3]、炎症反应[4]、表观遗传学修饰[5]、自噬[6-7]等。近年来研究[8]表明氧化应激是DKD足细胞损伤的关键因素。

活性氧(reactive oxygen species，ROS)是体内一类氧的单电子还原产物，包括氧的一电子还原产物超氧阴离子、二电子还原产物过氧化氢、三电子还原产物羟基自由基以及一氧化氮等。正常人体内氧化作用与抗氧化作用维持相互平衡，在病理条件下，如高糖环境、人体内氧化作用过强或者抗氧化作用低下，会造成体内ROS产生过多，产生大量氧化中间产物，然后通过一系列的信号转导途径，导致肾足细胞损伤[9]。总结氧化应激介导DKD足细胞的损伤机制可为DKD的治疗提供新的思路。

1. DKD足细胞损伤的主要表现

足细胞是终末分化的肾小球上皮细胞，从外部包裹肾小球毛细血管袢，提供物理支持和分泌细胞因子。足细胞向外延展形成以微管蛋白为基础的粗大的初级足突和以肌动蛋白为基础的细小的相互交错的次级足突。相邻足细胞的足突之间的相互连接是通过一种特殊的细胞间连接实现的，这种连接称为裂孔隔膜(slit diaphragm，SD)。

1.1. 足细胞SD蛋白分子的表达降低

SD是构成肾小球滤过膜的重要部分，由肾病蛋白、裂隙膜蛋白、CD2相关蛋白(CD2 associated protein，CD2AP)和肌动蛋白结合蛋白α-actitinin 4等组成。研究[10-12]发现糖尿病患者及动物模型肾病蛋白、裂隙膜蛋白、CD2AP的表达均有显著降低，并与蛋白尿及肾病的进展有密切关系。

1.2. 足突融合、丢失与足细胞数量减少、密度减小

研究[13-14]表明：在DKD早期进程中，足突融合、足细胞脱落、凋亡和抑制足细胞增殖导致的足细胞数量和密度减少，是DKD早期微量尿蛋白产生的主要损伤表现。

2. DKD中的ROS来源

2.1. 烟酰胺腺嘌呤二核苷酸磷酸氧化酶

烟酰胺腺嘌呤二核苷酸磷酸(nicotinamide adenine dinucleotide phosphate，NADPH)氧化酶(NADPH oxidases，NOx)、一氧化氮合酶、黄嘌呤氧化酶等均可产生活性氧，而NOx是细胞ROS的主要来源。NOx家族由7种亚型(NOx1-5和Duox1-2)组成，它们在体内的分布随物种和组织的不同而不同[15]。多项研究[16-19]表明：NOx1、NOx4、NOx5的过度表达会引起肾小球足细胞损伤，促进DKD的发生、发展。在高糖的刺激下，机体会产生大量的晚期糖基化终末产物(advanced glycation end products，AGEs)并逐渐在细胞内累积，随后与晚期糖基化产物受体(advanced glycation end product receptor，RAGE)结合，激活NOx，产生大量的ROS；研究[20]发现RAGE适配子可通过阻断AGEs-RAGE轴减少ROS的产生，进而延缓DKD的发生、发展。高糖还可通过直接促进RNA结合蛋白人类抗原R(RNA-binding protein human antigen R，HuR)与NOx4 mRNA结合，介导NOx4翻译上调，产生ROS[16]。此外，机体还可通过多元醇途径[21]和蛋白激酶C(protein kinase C，PKC)途径[22]激活NOx，从而导致ROS产生过多。因此，抑制NOx，从而减少ROS的产生，被认为是治疗DKD的一种新选择。

已有研究[23]表明NOx1/4抑制剂GKT137831对小鼠DKD模型有良好的治疗效果。然而，一项关于GKT137831对DKD患者影响的研究[24]进入了2期临床试验，该试验招募155名DKD患者，随访12周，主要考察尿白蛋白/肌酐比值较基线的变化，结果表明：GKT137831具有良好的安全性，即GKT137831组患者不良事件发生率低，但尿白蛋白/肌酐比值较基线没有显著差异，肾获益不明显。APX-115是一种新型泛NOx(pan-NOx)抑制剂，有研究[25]表明APX-115在DKD实验动物模型中对肾功能有明显的改善。因此评估pan-NOx抑制剂对DKD患者的疗效研究有一定的前景。

2.2. 线粒体途径

线粒体是ROS产生的重要场所。在线粒体中，柠檬酸循环产生的还原型烟酰胺腺嘌呤二核苷酸(nicotinamide adenine dinucleotide，NADH)和还原型黄素腺嘌呤二核苷酸(flavin adenine dinucleotide，FADH2)为电子传递链提供电子，并在线粒体内膜上形成质子梯度。当DKD患者的细胞内葡萄糖浓度升高时，或者游离的饱和脂肪酸浓度增高时，质子梯度过量增高会抑制电子从辅酶Q到电子传递链复合物Ⅲ的传递，导致电子传递到氧分子上，产生ROS，从而介导DKD足细胞损伤[26]。

过氧化物酶体增殖物激活受体γ共激活因子1(peroxisome proliferator-activated receptor γ coactivator-1，PGC-1)是线粒体生物合成的主要调控因子，PGC-1α亚型对维持线粒体功能和减少线粒体ROS生成具有重要作用。研究[27]表明：在DKD患者中，线粒体活性受到抑制，PGC-1α mRNA表达下降，ROS的产生增加。G蛋白偶联胆汁酸受体5(G protein-coupled bile acid receptor，TGR5)是肾中PGC-1α的重要调节因子，TGR5可通过激活AMP活化蛋白激酶(AMP-activated protein kinase，AMPK)磷酸化和沉默调节蛋白1(sirtuin 1，SIRT1)去乙酰化这两条路径激活 PGC-1α[28]。使用TGR5特异性激动剂INT-777可诱导 SIRT1表达，通过激活其下游足细胞PGC-1α表达来维持正常线粒体功能，从而减少DKD小鼠ROS的产生和足细胞丢失[29]。TGR5/SIRT/PGC-1α通路在抑制DKD进展中发挥了重要作用，可能会成为治疗DKD的新靶点。

3. ROS介导DKD足细胞的损伤机制

3.1. ROS介导足细胞凋亡

在DKD小鼠中，ROS产生增多的同时，一些凋亡信号通路的蛋白分子，如蛋白53(protein 53，p53)、B细胞淋巴瘤/白血病-2(B cell lymphoma/leukmia-2，Bcl-2)相关X蛋白(Bcl-2 associated X protein，Bax)、胱天蛋白酶-3(caspase 3)表达增加。高血糖诱导产生的ROS通过激活c-Src激酶，进而激活足细胞特异性表皮生长因子受体(epidermal growth factor receptor，EGFR)，从而促进EGFR活化依赖的细胞外调节蛋白激酶(extracellular regulated protein kinases，ERK)磷酸化，进一步激活TGF-β-smad2/3信号通路，下调Bcl-2的表达，上调caspase 3的表达，导致足细胞凋亡[30]，这可能是DKD发展过程中足细胞功能障碍和数量丢失的关键机制。Eid等[31]发现在DM小鼠的足细胞中，AMPK磷酸化水平降低，NOx4和p53表达增强，足细胞凋亡现象明显。其机制可能是高血糖使AMPK失活，上调NOx4，增强NOx4活性，ROS产生增多，增强p53表达，并促使足细胞凋亡。使用AMPK药理激活剂5-氨基咪唑-4-羧酰胺-1-核苷(aminoimidazole-4-carboxamide-1-riboside 5-aminoimi-dazole-4-carboxamide-1-riboside，AICAR)可阻断高糖诱导的NOx4活性增强和p53的表达，减轻DKD小鼠足细胞凋亡，从而显著减少蛋白尿。ROS还可增加p38丝裂原活化蛋白激酶(p38 mitogen activated protein kinase，p38 MAPK)表达，从而激活促凋亡的p38 MAPK通路，激活下游效应分子caspase 3，介导足细胞凋亡[32]。研究[32]发现使用多巴胺1受体(dopamine 1 receptor，D1R)激动剂SKF38393可通过调节蛋白激酶A(protein kinase A，PKA)/NOX-5/p38 MAPK轴减轻DKD小鼠足细胞氧化应激损伤和凋亡。此外，线粒体分裂参与了线粒体膜蛋白的泄漏和细胞凋亡的早期阶段[33]，动力相关蛋白(dynamin-related protein，Drp1)作为一个大的GTP酶，在线粒体分裂和促进高糖诱导的足细胞凋亡中也发挥了重要作用[34]。研究[35]发现在DKD中，ROS可通过激活Drp1，促进线粒体释放细胞色素C和激活caspase 3，导致线粒体分裂，介导足细胞凋亡，而虎杖苷(polydatin，PD)可以通过抑制ROS的产生、下调Drp1的表达来减轻高糖诱导的DKD小鼠足细胞凋亡。这可能是除了代谢控制之外，干预氧化应激对DKD的另一种辅助治疗机制。

3.2. ROS介导足细胞SD损伤

ROS通过上调瞬时受体电位阳离子通道蛋白(transient receptor potential canonical，TRCP)影响细胞内Ca2+浓度[36]介导的DKD足细胞SD损伤。TRCP是一种Ca2+通道，该蛋白通道是氧化还原敏感性蛋白，存在于肾各种固有细胞膜上，受ROS调控[37]，激活可导致Ca2+内流。足细胞中主要表达TRCP3和TRCP6，而TRCP6已被证明可通过调节钙稳态来调节足细胞的功能，特别是在DKD中可发挥重要作用[38-40]。在足细胞中，高血糖激活NOx产生的ROS可上调TRCP6，使细胞内Ca2+增高，胞内过多的Ca2+可破坏足细胞的收缩结构和肌动蛋白骨架，导致SD结构和功能障碍，从而导致超滤系数的改变，产生蛋白尿[36]。然而ROS能否通过影响内质网膜上Ca2+通道和腔内Ca2+浓度，诱导内质网应激，从而介导足细胞损伤、凋亡，但尚需进一步研究证明。研究[41]发现牛磺酸处理能够抑制小鼠足细胞TRPC6的表达，可减轻高糖诱导的足细胞损伤。

4. 抗氧化系统的调控在DKD足细胞损伤中的作用

抗氧化系统由超氧化物歧化酶(superoxide dismutase，SOD)、硫氧还蛋白过氧化物酶(thioredoxin peroxidase，TPx)、谷胱甘肽过氧化酶(glutathione peroxidase，GSH-Px)和过氧化氢酶等抗氧化酶组成，可通过抑制ROS的产生，减轻DKD足细胞损伤。机体可通过调控抗氧化酶的转录、活性以及表观遗传学修饰影响ROS的产生，进一步影响DKD足细胞损伤的发生、发展。

4.1. 抗氧化酶的转录、活性调控在DKD足细胞损伤中的作用

核因子红系相关因子2(nuclear factor erythroid related factor 2，Nrf2)通过促进抗氧化酶的转录，减少ROS的产生，减轻DKD足细胞损伤。Nrf2是一种碱性亮氨酸拉链转录因子，在生理情况下Nrf2与阻遏蛋白Kelch样ECH相关蛋白-1(Kelch-like ECH-associated protein-1，Keap1)形成Nrf2-Keap1复合体，稳定存在于细胞质。Nrf2-Keap1是机体的一种自我保护防御系统，当ROS产生过多时，Nrf2由结合状态变为游离状态，Nrf2移位至细胞核，与启动子区域的抗氧化反应元件(anti-oxidative response element，ARE)结合，启动各种抗氧化基因的转录[42]，如启动主要抗氧化系统SOD、谷胱甘肽S转移酶(glutathione-S-transferases，GSTs)和醌氧化还原酶1(quinone oxidoreductase 1，Nqo1)[43]等基因的转录，增强细胞清除ROS的能力，维持人体氧化还原的平衡，促进氧自由基的清除，减轻DKD足细胞损伤，延缓DKD的发生、发展。Nrf2/ARE途径是近年来发现的最重要的内源性抗氧化应激途径。

NADPH是抗氧化系统的关键辅助因子，而葡萄糖-6-磷酸脱氢酶(glucose-6-phosphate dehydrogenase，G6PD)是生成NADPH的关键酶，G6PD表达降低可影响抗氧化酶发挥作用，使ROS产生增加，加重DKD足细胞损伤，而过表达G6PD可减轻DKD小鼠足细胞损伤。NADPH可将氧化的谷胱甘肽和氧化的硫氧还蛋白转变为还原形式，是抗氧化系统谷胱甘肽和硫氧还蛋白体系清除ROS所必需的辅助因子，而磷酸戊糖途径是NADPH产生的主要途径，其中G6PD是限速酶[44]。研究[45]发现在DKD小鼠足细胞中，G6PD表达降低，ROS产生增多，细胞凋亡增加，而过表达G6PD可减轻DKD小鼠足细胞氧化应激损伤和凋亡。高糖不影响足细胞G6PD mRNA的表达，G6PD蛋白表达降低是通过泛素蛋白酶体途径所介导的。E3泛素连接酶VHL(von Hippel-Lindau)可直接与G6PD结合，通过泛素化G6PD上的K366和K403降解G6PD。然而，也有研究[46-47]表明G6PD在DM动物的胰岛、脂肪组织和肝中表达上调，G6PD的过度激活将通过向NOx提供NADPH来刺激ROS的产生。其研究结果之间的差异表明，G6PD在不同组织中的表达可能对高血糖的反应不同，G6PD的过度激活或缺乏会根据细胞类型的不同而通过不同的机制诱导ROS的积累。总之，VHL/G6PD轴在维持DKD的足细胞功能和结构方面起着重要作用，进一步探索VHL/G6PD作为DKD新的治疗靶点是有一定前景的。

4.2. 抗氧化酶的表观遗传学修饰在DKD足细胞损伤中的作用

表观遗传学修饰是指表观遗传学改变[DNA甲基化、组蛋白修饰和非编码RNA(如miRNA)]对表观基因组基因表达的调节，这种调节不依赖基因序列的改变，抗氧化系统的表观遗传学修饰在调控ROS的产生、减轻DKD足细胞损伤中起重要作用。组蛋白甲基转移酶增强子2(histone methyltransferase enzyme enhancer of zestehomolog 2，EZH2)可通过增强Pax6启动子上的组蛋白H3赖氨酸27三甲基化(histone H3 lysine 27 trimethylation，H3K27me3)的表达、沉默转录因子Pax6、抑制抗氧化抑制剂硫氧还蛋白相互作用蛋白(thioredoxin interacting protein，TXNIP)的表达，从而减少ROS的产生[48]。而在DKD中，EZH2下降，H3K27me3减少，TXNIP的表达增加，ROS累积增多，导致足细胞损伤和蛋白尿[48]。此外，H3K27me3减少还可通过激活Notch途径，介导足细胞去分化和凋亡[49-50]。上述研究表明了表观遗传学修饰对DKD足细胞的影响，并为DKD的治疗提供了新思路。

5. 结 语

DKD是导致ESKD的重要原因，其发病机制复杂，尽管对DKD患者进行了积极的临床干预，包括严格的血糖控制、血压控制，并采用了血管紧张素转换酶抑制、血管紧张素II受体或盐皮质激素受体拮抗剂、钠-葡萄糖协同转运蛋白2(sodium-glucose co-transporter 2，SGLT-2)抑制剂，但大多数患者的肾损伤仍会加重。足细胞损伤是DKD进展的关键环节，而氧化应激是介导DKD足细胞损伤的重要机制。氧化应激涉及多种信号通路，导致足细胞SD蛋白分子异常、足突融合以及足细胞凋亡、脱落等损伤表现，促进DKD的进展。但具体哪条信号通路在氧化应激介导DKD足细胞损伤机制中占主导作用，尚无明确结论。虽然抗氧化应激药物可以减轻DKD小鼠足细胞的损伤，延缓DKD的进展，但抗氧化应激药物对DKD患者的影响研究大多处于早期临床试验阶段，且存在研究对象数量偏少、随访时间较短等缺陷，因此抗氧化应激药物或化合物对DKD患者的预后影响亟待进一步的多中心、大规模前瞻性临床研究。本文所介绍的氧化应激信号通路和抗氧化系统的调控因素可能为治疗DKD提供新的思路。

基金资助

国家自然科学基金(82073918，82173877)；湖南省重点研发计划项目(2021SK2015)；湖南省自然科学基金(2021JJ41039)。

This work was supported by the National Natural Science Foundation (82073918, 82173877), the Key Research and Development Plan Project of Hunan Province (2021SK2015), and the Natural Science Foundation of Hunan Province (2021JJ41039), China.

利益冲突声明

作者声称无任何利益冲突。

原文网址

http://xbyxb.csu.edu.cn/xbwk/fileup/PDF/2021121403.pdf

参考文献

  • 1. Umanath K, Lewis JB. Update on diabetic nephropathy: Core curriculum 2018[J]. Am J Kidney Dis, 2018, 71(6): 884-895. [DOI] [PubMed] [Google Scholar]
  • 2. Fu Y, Sun Y, Wang M, et al. Elevation of JAML promotes diabetic kidney disease by modulating podocyte lipid metabolism[J]. Cell Metab, 2020, 32(6): 1052-1062. [DOI] [PubMed] [Google Scholar]
  • 3. Hong Q, Zhang L, Das B, et al. Increased podocyte Sirtuin-1 function attenuates diabetic kidney injury[J]. Kidney Int, 2018, 93(6): 1330-1343. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4. Zhong Y, Lee K, Deng Y, et al. Arctigenin attenuates diabetic kidney disease through the activation of PP2A in podocytes[J]. Nat Commun, 2019, 10(1): 157-160. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5. Liu M, Liang K, Zhen J, et al. Sirt6 deficiency exacerbates podocyte injury and proteinuria through targeting Notch signaling[J]. Nat Commun, 2017, 8(1): 413. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 6. Li Y, Pan Y, Cao S, et al. Podocyte EGFR inhibits autophagy through upregulation of rubicon in Type 2 diabetic nephropathy[J]. Diabetes, 2021, 70(2): 562-576. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7. Dusabimana T, Kim SR, Park EJ, et al. P2Y2R contributes to the development of diabetic nephropathy by inhibiting autophagy response[J]. Mol Metab, 2020, 42: 101089. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8. Lee E, Lee HS. Peroxidase expression is decreased by palmitate in cultured podocytes but increased in podocytes of advanced diabetic nephropathy[J]. J Cell Physiol, 2018, 233(12): 9060-9069. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9. Duni A, Liakopoulos V, Roumeliotis S, et al. Oxidative stress in the pathogenesis and evolution of chronic kidney disease: Untangling Ariadne's thread[J]. Int J Mol Sci, 2019, 20(15): 3711 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10. Wang S, Yang Y, He X, et al. Cdk5-mediated phosphorylation of Sirt1 contributes to podocyte mitochondrial dysfunction in diabetic nephropathy[J]. Antioxid Redox Signal, 2021, 34(3): 171-190. [DOI] [PubMed] [Google Scholar]
  • 11. Zhou Z, Wan J, Hou X, et al. MicroRNA-27a promotes podocyte injury via PPARγ-mediated β-catenin activation in diabetic nephropathy[J]. Cell Death Dis, 2017, 8(3): 2658. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12. Li S, Liu X, Lei J, et al. Crocin protects podocytes against oxidative stress and inflammation induced by high glucose through inhibition of NF-κB[J]. Cell Physiol Biochem, 2017, 42(4): 1481-1492. [DOI] [PubMed] [Google Scholar]
  • 13. Zhou L, Chen X, Lu M, et al. Wnt/β-catenin links oxidative stress to podocyte injury and proteinuria[J]. Kidney Int, 2019, 95(4): 830-845. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14. Denhez B, Rousseau M, Dancosst DA, et al. Diabetes-induced DUSP4 reduction promotes podocyte dysfunction and progression of diabetic nephropathy[J]. Diabetes, 2019, 68(5): 1026-1039. [DOI] [PubMed] [Google Scholar]
  • 15. Holterman CE, Boisvert NC, Thibodeau JF, et al. Podocyte NADPH oxidase 5 promotes renal inflammation regulated by the Toll-like receptor pathway[J]. Antioxid Redox Signal, 2019, 30(15): 1817-1830. [DOI] [PubMed] [Google Scholar]
  • 16. Shi Q, Lee DY, Féliers D, et al. Interplay between RNA-binding protein HuR and Nox4 as a novel therapeutic target in diabetic kidney disease[J]. Mol Metab, 2020, 36: 100968. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17. Rajaram RD, Dissard R, Jaquet V, et al. Potential benefits and harms of NADPH oxidase Type 4 in the kidneys and cardiovascular system[J]. Nephrol Dial Transplant, 2019, 34(4): 567-576. [DOI] [PubMed] [Google Scholar]
  • 18. Liang Y, Liu H, Fang Y, et al. Salvianolate ameliorates oxidative stress and podocyte injury through modulation of NOX4 activity in db/db mice[J]. J Cell Mol Med, 2021, 25(2): 1012-1023. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19. Shao X, Zhang X, Hu J, et al. Dopamine 1 receptor activation protects mouse diabetic podocytes injury via regulating the PKA/NOX-5/p38 MAPK axis[J]. Exp Cell Res, 2020, 388(2): 111849. [DOI] [PubMed] [Google Scholar]
  • 20. Matsui T, Higashimoto Y, Nishino Y, et al. RAGE-aptamer blocks the development and progression of experimental diabetic nephropathy[J]. Diabetes, 2017, 66(6): 1683-1695. [DOI] [PubMed] [Google Scholar]
  • 21. Hodgkinson AD, Millward BA, Demaine AG. Association of the p22phox component of NAD(P)H oxidase with susceptibility to diabetic nephropathy in patients with Type 1 diabetes[J]. Diabetes Care, 2003, 26(11): 3111-3115. [DOI] [PubMed] [Google Scholar]
  • 22. Warren AM, Knudsen ST, Cooper ME. Diabetic nephropathy: an insight into molecular mechanisms and emerging therapies[J]. Expert OpinTher Targets, 2019, 23(7): 579-591. [DOI] [PubMed] [Google Scholar]
  • 23. Gray SP, Jha JC, Kennedy K, et al. Combined NOX1/4 inhibition with GKT137831 in mice provides dose-dependent reno- and atheroprotection even in established micro- and macrovascular disease[J]. Diabetologia, 2017, 60(5): 927-937. [DOI] [PubMed] [Google Scholar]
  • 24. National Institutes of Health . Safety and efficacy of oral GKT137831 in patient with Type 2 diabetes and albuminuria[EB/OL]. (2015-09-09) [2021-03-24] https://www.businesswire. com/news/home/20150909005080/en/Genkyotex-AnnouncesTop- Line-Results-Phase-2-Clinical.
  • 25. Cha JJ, Min HS, Kim KT, et al. APX-115, a first-in-class pan-NADPH oxidase (Nox) inhibitor, protects db/db mice from renal injury[J]. Lab Invest, 2017, 97(4): 419-431. [DOI] [PubMed] [Google Scholar]
  • 26. Brownlee M. Biochemistry and molecular cell biology of diabetic complications[J]. Nature, 2001, 414(6865): 813-820. [DOI] [PubMed] [Google Scholar]
  • 27. Wang XX, Wang D, Luo Y, et al. FXR/TGR5 dual agonist prevents progression of nephropathy in diabetes and obesity[J]. J Am Soc Nephrol, 2018, 29(1): 118-137. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28. Fernandez-Marcos PJ, Auwerx J. Regulation of PGC-1α, a nodal regulator of mitochondrial biogenesis[J]. Am J Clin Nutr, 2011, 93(4): 884-890. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29. Wang XX, Edelstein MH, Gafter U, et al. G protein-coupled bile acid receptor TGR5 activation inhibits kidney disease in obesity and diabetes[J]. J Am Soc Nephrol, 2016, 27(5): 1362-1378. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30. Chen J, Chen JK, Harris RC. EGF receptor deletion in podocytes attenuates diabetic nephropathy[J]. J Am Soc Nephrol, 2015, 26(5): 1115-1125. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31. Eid AA, Ford BM, Block K, et al. AMP-activated protein kinase (AMPK) negatively regulates Nox4-dependent activation of p53 and epithelial cell apoptosis in diabetes[J]. J Biol Chem, 2010, 285(48): 37503-37512. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32. Shao X, Zhang X, Hu J, et al. Dopamine 1 receptor activation protects mouse diabetic podocytes injury via regulating the PKA/NOX-5/p38 MAPK axis[J]. Exp Cell Res, 2020, 388(2): 111849. [DOI] [PubMed] [Google Scholar]
  • 33. Su J, Gao C, Xie L, et al. Astragaloside II ameliorated podocyte injury and mitochondrial dysfunction in streptozotocin-induced diabetic rats[J]. Front Pharmacol, 2021, 12: 638422. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34. Katusic ZS, Austin SA. Endothelial nitric oxide: protector of a healthy mind[J]. Eur Heart J, 2014, 35(14): 888-894. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35. Ni Z, Tao L, Xiaohui X, et al. Polydatin impairs mitochondria fitness and ameliorates podocyte injury by suppressing Drp1 expression[J]. J Cell Physiol, 2017, 232(10): 2776-2787. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36. Möller CC, Wei C, Altintas MM, et al. Induction of TRPC6 channel in acquired forms of proteinuric kidney disease[J]. J Am Soc Nephrol, 2007, 18(1): 29-36. [DOI] [PubMed] [Google Scholar]
  • 37. Trebak M, Ginnan R, Singer HA, et al. Interplay between calcium and reactive oxygen/nitrogen species: an essential paradigm for vascular smooth muscle signaling[J]. Antioxid Redox Signal, 2010, 12(5): 657-674. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 38. Ilatovskaya DV, Blass G, Palygin O, et al. A NOX4/TRPC6 pathway in podocyte calcium regulation and renal damage in diabetic kidney disease[J]. J Am Soc Nephrol, 2018, 29(7): 1917-1927. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 39. Ilatovskaya DV, Levchenko V, Lowing A, et al. Podocyte injury in diabetic nephropathy: implications of angiotensin II-dependent activation of TRPC channels[J]. Sci Rep, 2015, 5: 17637. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40. Spires D, Ilatovskaya DV, Levchenko V, et al. Protective role of Trpc6 knockout in the progression of diabetic kidney disease[J]. Am J Physiol Renal Physiol, 2018, 315(4): 1091-1097. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 41. Zhang R, Wang X, Gao Q, et al. Taurine supplementation reverses diabetes-induced podocytes injury via modulation of the CSE/TRPC6 axis and improvement of mitochondrial function[J]. Nephron, 2020, 144(2): 84-95. [DOI] [PubMed] [Google Scholar]
  • 42. Wang J, Yang Y, Li Y, et al. Computational study exploring the interaction mechanism of benzimidazole derivatives as potent cattle bovine viral diarrhea virus inhibitors[J]. J Agric Food Chem, 2016, 64(29): 5941-5950. [DOI] [PubMed] [Google Scholar]
  • 43. Mutter FE, Park BK, Copple IM. Value of monitoring Nrf2 activity for the detection of chemical and oxidative stress[J]. Biochem Soc Trans, 2015, 43(4): 657-662. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 44. Tao R, Zhao Y, Chu H, et al. Genetically encoded fluorescent sensors reveal dynamic regulation of NADPH metabolism[J]. Nat Methods, 2017, 14(7): 720-728. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 45. Wang M, Hu J, Yan L, et al. High glucose-induced ubiquitination of G6PD leads to the injury of podocytes[J]. FASEB J, 2019, 33(5): 6296-6310. [DOI] [PubMed] [Google Scholar]
  • 46. Park J, Choe SS, Choi AH, et al. Increase in glucose-6-phosphate dehydrogenase in adipocytes stimulates oxidative stress and inflammatory signals[J]. Diabetes, 2006, 55(11): 2939-2949. [DOI] [PubMed] [Google Scholar]
  • 47. Gupte RS, Floyd BC, Kozicky M, et al. Synergistic activation of glucose-6-phosphate dehydrogenase and NAD(P)H oxidase by Src kinase elevates superoxide in Type 2 diabetic, Zucker fa/fa, rat liver[J]. Free Radic Biol Med, 2009, 47(3): 219-228. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 48. Siddiqi FS, Majumder S, Thai K, et al. The histone methyltransferase enzyme enhancer of Zeste homolog 2 protects against podocyte oxidative stress and renal injury in diabetes[J]. J Am Soc Nephrol, 2016, 27(7): 2021-2034. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 49. Majumder S, Thieme K, Batchu SN, et al. Shifts in podocyte histone H3K27me3 regulate mouse and human glomerular disease[J]. J Clin Invest, 2018, 128(1): 483-499. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 50. Niranjan T, Bielesz B, Gruenwald A, et al. The Notch pathway in podocytes plays a role in the development of glomerular disease[J]. Nat Med, 2008, 14(3): 290-298. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Central South University Medical Sciences are provided here courtesy of Central South University

RESOURCES