Efficacy/mechanisms of curcumin in diabetic nephropathy

描述(申请人提供)：糖尿病肾病(DN)是终末期肾病最常见的原因。蛋白尿(Ualb)通过不明确的机制加重糖尿病肾病。足细胞(podocytes，PODO)通过信号事件介导的肌动蛋白细胞骨架(Actskn，Actskn)改变来调节Ualb。我们发现，磷酸化的p38MAPK诱导PODO热休克蛋白25(HSP25，啮齿类动物；HSP27，人类)的双磷酸化(P2)，以响应急性血糖应激，以适应维持PODO Actskn和防止Ualb。后来，适应失败了。我们还表明，花生四烯酸代谢的12/15脂氧合酶(LO)途径在PODO和系膜细胞中介导葡萄糖、血管紧张素II、PDGF和转化生长因子-β的作用，所有这些都是潜在的糖尿病肾病。12/15LO基因敲除的DM小鼠表现出肾皮质转化生长因子-β和结缔组织生长因子mRNAs的抑制、转化生长因子-β的表达、Smad2/3信号转导和蛋白尿。因此，我们的数据提示在糖尿病肾病中存在HSP25和12/15LO通路。证据与这些途径有关：化学LO抑制刺激HSP27，在两者所带来的益处之间提供关键的致病联系。膳食香料姜黄素的生物学作用模拟HSP25和12/15LO的作用。增加HSP27，抑制LO和转化生长因子-β。在短期糖尿病大鼠中，姜黄素可抑制蛋白尿并改善肾脏组织学。在优化姜黄素产品、剂量和给药途径的初步实验后，我们将检验这样的假设，即姜黄素将：1)改善长期糖尿病小鼠的糖尿病肾病；2)通过增强HSP25并抑制12/15LO和转化生长因子-β，从而保护Actskn并抑制细胞外基质的合成；3)表现出多种有益的作用，使其与HSP27的过表达或12/15LO的单独抑制相媲美或优于单独作为治疗的HSP27；以及4)诱导HSP27与12/15LO之间的相互作用。利用新的HSP27功能获得和12/15LO功能丧失的小鼠模型和最新的分子技术，这些研究评估了姜黄素的疗效并确定了潜在的作用机制。热休克蛋白27、转化生长因子-β和12/15LO现在不能直接通过药物改变。在第一阶段试验中，人类对姜黄素的耐受性很好，剂量高达每天8克。阿尔茨海默病的第二阶段试验正在进行中。实验性糖尿病肾病的疗效可以迅速转化为患者的可测试疗法。

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.