Efficacy/mechanisms of curcumin in diabetic nephropathy

描述（由申请人提供）：糖尿病（DM）肾病（DN）是终末期肾病最常见的原因。白蛋白尿（Ualb）通过不明确的机制加重DN。足细胞（podo）通过由信号事件介导的肌动蛋白细胞骨架（Actskn）变化来调节Ualb。我们发现磷酸化p38 MAPK诱导足热休克蛋白25（HSP 25，啮齿动物; HSP 27，人类）的双磷酸化（p2），以响应急性血糖应激，适应维持足Actskn和防止Ualb。适应失败后。我们还发现，花生四烯酸代谢的12/15脂氧合酶（LO）途径介导足细胞和系膜细胞中的葡萄糖、血管紧张素II、PDGF和TGF-β作用，所有这些都是DN的基础。12/15 LO敲除DM小鼠表现出肾皮质TGF-β和CTGF mRNA、TGF-β表达、Smad 2/3信号传导和蛋白尿的抑制。因此，我们的数据暗示HSP 25和12/15 LO通路在DN中。证据涉及的途径：化学LO抑制刺激热休克蛋白27，提供了一个关键的发病机制之间的联系所赋予的每一个好处。膳食香料姜黄素的生物学作用模拟HSP 25和12/15 LO作用。它增加HSP 27并抑制LO和TGF-β。在短期糖尿病大鼠中，姜黄素抑制蛋白尿，改善肾脏组织学。在优化姜黄素产品、剂量和给药途径的初步实验之后，我们将验证姜黄素将：1）改善长期DM小鼠的DN; 2）通过增强HSP 25和抑制12/15 LO和TGF-β来保护Actskn并抑制细胞外基质合成; 3）表现出多种有益效果，使其与单独作为治疗的HSP 27过表达或12/15 LO抑制相当或上级;和4）诱导连接HSP 27和12/15 LO的相互作用。使用新的HSP 27功能获得和12/15 LO功能丧失小鼠模型和最先进的分子技术，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12/15 LO现在不能直接通过药物进行修饰。在1期试验中，人类对姜黄素的耐受性良好，剂量高达8 gm/天。阿尔茨海默病的第二阶段试验正在进行中。实验性DN的疗效可以迅速转化为患者的可测试治疗。

DESCRIPTION (provided by applicant): 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 1 trials, 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.