Efficacy/mechanisms of curcumin in diabetic nephropathy

糖尿病肾病是终末期肾病最常见的病因。蛋白尿(Ualb) 通过不明确的机制加重糖尿病肾病。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。我们发现磷酸化的p38MAPK诱导双磷酸化(P2)。 Podo热休克蛋白25(HSP25，啮齿动物；HSP27，人类)对急性血糖应激的反应 适应以维持Podo Actskn和预防Ualb。后来，适应失败了。我们还表明，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和转化生长因子-2。 PODO和系膜细胞中的β作用，都是潜在的糖尿病肾病。12/15LO基因敲除的糖尿病小鼠表现出抑制 肾皮质转化生长因子-β和结缔组织生长因子mRNAs、转化生长因子-β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。与这些途径相关的证据：化学损失 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。这个 膳食香料姜黄素的生物学作用模拟HSP25和12/15LO的作用。它增加了HSP27和 抑制LO和转化生长因子-β。在短期糖尿病大鼠中，姜黄素抑制蛋白尿并改善肾脏 组织学。经过优化姜黄素产品、剂量和给药途径的初步实验，我们 将验证这样的假设：姜黄素将：1)改善长期糖尿病小鼠的糖尿病肾病；2)保留Actskn 通过增强HSP25，抑制12/15LO和转化生长因子-β，抑制细胞外基质合成；3) 表现出多种有益的效果，使其可与HSP27过度表达或 4)诱导HSP27与12/15LO之间的相互作用。使用小说 Hsp27功能的获得和12/15LO功能的丧失小鼠模型和最新分子 这些研究评估了姜黄素的疗效，并确定了姜黄素的潜在作用机制。HSP27， 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 姜黄素的剂量可达每天8克。阿尔茨海默病的第二阶段试验正在进行中。药效在 实验性糖尿病肾病可以迅速转化为一种可测试的治疗方法。

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.