Efficacy/mechanisms of curcumin in diabetic nephropathy

描述（由申请人提供）：糖尿病（DM）肾病（DN）是终末期肾病的最常见原因。蛋白尿 (Ualb) 通过不明确的机制加剧 DN。足细胞 (podo) 通过信号事件介导的肌动蛋白细胞骨架 (Actskn) 变化调节 Ualb。我们发现，磷酸化 p38MAPK 会诱导 podo 热休克蛋白 25（HSP25，啮齿动物；HSP27，人类）双磷酸化 (p2)，以响应急性血糖应激，以适应维持 podo Actskn 并预防 Ualb。后来适配失败。我们还表明，花生四烯酸代谢的 12/15 脂氧合酶 (LO) 途径介导足部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。 12/15LO 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，我们的数据表明 DN 中存在 HSP25 和 12/15LO 通路。有证据表明这些途径：化学 LO 抑制会刺激 HSP27，从而在每种途径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作用模拟 HSP25 和 12/15LO 作用。它增加 HSP27 并抑制 LO 和 TGF-β。在患有短期糖尿病的大鼠中，姜黄素抑制蛋白尿并改善肾脏组织学。经过初步实验优化姜黄素产品、剂量和给药途径，我们将检验姜黄素将：1）改善长期糖尿病小鼠的 DN； 2）通过增强HSP25和抑制12/15LO和TGF-β来保留Actskn并抑制细胞外基质合成； 3) 表现出多种有益效果，使其与单独使用 HSP27 过表达或 12/15LO 抑制疗法相当或更好； 4) 诱导连接 HSP27 和 12/15LO 的相互作用。这些研究利用新型 HSP27 功能获得和 12/15LO 功能丧失小鼠模型和最先进的分子技术，评估功效并确定姜黄素作用的潜在机制。 HSP27、TGF-β 和 12/15LO 现在无法通过药物直接修改。在第一阶段试验中，人类对姜黄素的耐受性良好，剂量高达 8 克/天。阿尔茨海默病的二期试验正在进行中。实验性 DN 的疗效可以迅速转化为可用于患者的可测试疗法。

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.