Efficacy/mechanisms of curcumin in diabetic nephropathy

姜黄素治疗糖尿病肾病的功效/机制

• 批准号: 7496258
• 负责人: SHARON G ADLER
• 金额: $ 6.29万
• 依托单位: LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-30 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7496258
• 关键词: Actins; Acute; Adriamycin PFS; Albuminuria; Alzheimer' s Disease; Angiotensin II; Antioxidants; Appendix; Arachidonate 12-Lipoxygenase; Arachidonate 15-Lipoxygenase; Arts; Binding; Biological; Biological Factors; Biological Preservation; Cerebral Ischemia; Chemicals; Colitis; Collagen; Colon Carcinoma; Complementary DNA; Condition; Curcuma longa; Curcumin; Cytoskeleton; Data; Diabetic Nephropathy; Diabetic mouse; Diet; Disease model; Disruption; Dose; End stage renal failure; Enhancers; Epidermal Growth Factor; Event; Exhibits; Extracellular Matrix; F-Actin; Failure; Fibroblasts; Fibronectins; Filtration; G Actin; Glucose; HSPB1 gene; Heat shock proteins; Histology; Human; Hydroxyeicosatetraenoic Acids; I Kappa B-Alpha; In Vitro; JUN gene; Kidney; Kidney Diseases; Knock-out; Left; Link; Lipid Peroxidation; Lipoxygenase; Lipoxygenase Inhibitors; Maintenance; Malignant neoplasm of prostate; Measures; Mediating; Mediator of activation protein; Membrane; Messenger RNA; Metabolism; Modeling; Molecular; Molecular Models; Mouse Strains; Mus; NF-kappa B; Nuclear; Oral; PTGS2 gene; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Phase II Clinical Trials; Phosphorylation; Plant Components; Plasminogen Activator Inhibitor 1; Platelet-Derived Growth Factor; Principal Investigator; Protein Isoforms; Protein Overexpression; Proteins; Proteinuria; Publishing; Rattus; Reagent; Relative (related person); Research Personnel; Rodent; Role; Route; Score; Serum; Signal Pathway; Signal Transduction; Simulate; Small Interfering RNA; Spices; Streptozocin; Stress; Stress Fibers; Techniques; Testing; Transforming Growth Factor beta; Transgenic Mice; Transgenic Organisms; Translating; Wild Type Mouse; Work; analog; arachidonate; cancer cell; cell type; computerized data processing; connective tissue growth factor; crosslink; day; diabetic; gain of function; glomerular basement membrane; heat-shock factor 1; human TGFB1 protein; improved; in vivo; in vivo Model; inhibitor/antagonist; loss of function; mesangial cell; mouse model; novel; podocyte; prevent; programs; research study; response; thiobarbituric acid; transcription factor; transforming growth factor beta3; urinary

Diabetic (DM) nephropathy (DN) is the commonest cause of end stage renal disease. Albuminuria (Ualb) exacerbates DN by ill-defined mechanisms. Podocytes (podo) modulate Ualb via actin cytoskeleton (Actskn) chnages mediated by signaling events. We showed that phospho-p38MAPK induces biphosphorylation (p2) of podo heat shock protein 25 (HSP25, rodents; HSP27, humans) in response to acute glycemic stress, in an adaptation to maintain podo Actskn and prevent Ualb. Adaptation fails later. We also showed that the 12/15 lipoxygenase (LO) pathway of arachidonate metabolism mediates glucose, angiotensin II, PDGF, and TGF- beta actions in podo and mesangial cells, all underlying DN. 12/15LO knockout DM mice exhibit inhibition of renal cortical TGF-beta and CTGF mRNAs, TGF-beta expression, Smad 2/3 signaling, and proteinuria. Thus, our data implicate HSP25 and 12/15LO pathways in DN. Evidence relates the pathways: chemical LO inhibition stimulates HSP27, providing a key pathogenetic link between the benefits conferred by each. The biologic actions of the dietary spice curcumin simulate HSP25 and 12/15LO actions. It increases HSP27 and inhibits LO and TGF-beta. In rats with short-term DM, curcumin inhibited proteinuria and improved renal histology. After preliminary experiments to optimize curcumin product, dose, and route of administration, we will test the hypothesis that curcumin will: 1) Ameliorate DN in mice with long-term DM; 2) Preserve Actskn and inhibit extracellular matrix synthesis by enhancing HSP25 and inhibiting 12/15LO and TGF-beta; 3) Exhibit multiple salutary effects, making it comparable or superior to either HSP27 overexpression or 12/15LO inhibition alone as therapy; and 4) Induce interactions linking HSP27 and 12/15LO. Using novel HSP27 gain of function and 12/15LO loss of function mouse mdoels and state of the art molecular techniques, these studies assess efficacy and define underlying mechanisms of curcumin action. HSP27, TGF-beta, and 12/15LO are not now modifiable directly be medications. In Phase 1trials, humans tolerated curcumin well in doses up to 8 gm/day. A Phase 2 trial for Alzheimer disease is in progress. Efficacy in experimental DN could translate rapidly into a testable therapy for patients.

糖尿病肾病（diabetic nephropathy，DN）是终末期肾病最常见的病因。白蛋白尿（Ualb） 通过不明确的机制加重DN。足细胞（podo）通过肌动蛋白细胞骨架（Actskn）调节Ualb 由信号事件介导的变化。我们发现磷酸化p38MAPK诱导双磷酸化（p2） 足热休克蛋白25（HSP 25，啮齿类动物; HSP 27，人类）对急性血糖应激的反应， 适应以维持足Actskn和预防Ualb。适应失败后。我们还发现，12/15 花生四烯酸代谢的脂氧合酶（LO）途径介导葡萄糖、血管紧张素II、PDGF和TGF-β 1。 足细胞和系膜细胞的β作用，所有这些都是DN的基础。12/15LO敲除DM小鼠表现出对 肾皮质TGF-β和CTGF mRNA、TGF-β表达、Smad 2/3信号传导和蛋白尿。 因此，我们的数据暗示HSP 25和12/15LO通路在DN中。证据与途径有关：化学LO 抑制刺激HSP 27，提供了各自所赋予的益处之间的关键致病联系。的 食用香料姜黄素的生物学作用模拟HSP 25和12/15LO作用。它增加了HSP27， 抑制LO和TGF-β。在短期糖尿病大鼠中，姜黄素可抑制蛋白尿，改善肾脏 组织学经过初步的实验，以优化姜黄素产品，剂量和给药途径，我们 将测试姜黄素将：1）改善长期DM小鼠的DN; 2）保持Actskn 并通过增强HSP 25和抑制12/15LO和TGF-β来抑制细胞外基质合成; 3） 表现出多种有益的作用，使其与HSP 27过表达或HSP 28过表达相比相当或上级。 单独抑制12/15LO作为治疗;和4）诱导连接HSP 27和12/15LO的相互作用。使用新颖 HSP 27功能获得和12/15LO功能丧失小鼠模型和最新分子水平 技术，这些研究评估功效并定义姜黄素作用的潜在机制。HSP 27， TGF-β和12/15LO现在不能直接通过药物改变。在第一阶段的试验中， 姜黄素的剂量高达8克/天。阿尔茨海默病的第二阶段试验正在进行中。疗效 实验性DN可以迅速转化为患者的可测试疗法。

项目成果

The renin inhibitor aliskiren attenuates high-glucose induced extracellular matrix synthesis and prevents apoptosis in cultured podocytes.

肾素抑制剂阿利吉仑可减弱高葡萄糖诱导的细胞外基质合成并防止培养的足细胞凋亡。

• DOI: 10.1159/000322242
• 发表时间: 2011
• 期刊: Nephron. Experimental nephrology
• 作者: Phillips,LynettaM;Wang,Ying;Dai,Tiane;Feldman,DavidL;LaPage,Janine;Adler,SharonG
• 通讯作者: Adler,SharonG

Curcumin activates the p38MPAK-HSP25 pathway in vitro but fails to attenuate diabetic nephropathy in DBA2J mice despite urinary clearance documented by HPLC.

• DOI: 10.1186/1472-6882-10-67
• 发表时间: 2010-11-12
• 期刊: BMC complementary and alternative medicine
• 作者: Ma J;Phillips L;Wang Y;Dai T;LaPage J;Natarajan R;Adler SG
• 通讯作者: Adler SG