吡格列酮在肾脏中的抗衰老作用

收藏分享 2009-10-9 17:22| 发布者: tianniao| 查看数: 89| 评论数: 0

PPAR-r受体激动剂吡格列酮能够改善年龄相关的累积性肾脏损害
吡格列酮，一种过氧化物酶增殖子活化受体激动剂，是降糖药物中噻唑烷二酮类的一种，不会刺激内源性胰岛素的释放，但能够增加胰岛素介导的骨骼肌对葡萄糖的摄取并改善脂代谢紊乱。PPAR-r 受体激动剂在治疗非胰岛素依赖性的糖尿病患者是有效的。然而，PPAR-r受体激动剂还具有非代谢方面的作用，例如调节细胞分裂周期，抑制炎症反应以及调整细胞因子产物。作者先前的研究表明PPAR-r受体激动剂能够改善非糖尿病患者肾小球硬化，最近，有报道称吡格列酮在试验糖尿病家兔中肝脏和肾脏中具有拮抗氧化应激作用。
长期暴露在吡格列酮下能够提高线粒体功能，众所周知，线粒体在相关损伤后产生超过90%的活性氧簇，更重要的是有一项研究表明 PPAR-r基因多态性与PPAR-r活性和胰岛素敏感性以及人的寿命有关。然而，在增龄过程中PPAR的调节作用却报道甚少。因为增龄过程中PPARγ 表达减少以及噻唑烷二酮类有很多有益的作用，作者假设吡格列酮能够保护年龄相关的肾脏损伤。作者的研究结果实际上表明了激动PPARγ受体对增龄相关的肾脏损伤是有保护作用的。其作用机制可能与通过蛋白激酶C-β通路增加p66Shc磷酸化进而减少氧化应激反应有关。
再次，作者发现PPAR-r受体激动剂吡格列酮保护年龄相关的肾脏损伤，通过增加PPAR-r局部表达减少蛋白尿，增加肾小球滤过率，减少肾小球硬化，延缓细胞衰老。其根本的作用机制包括增加klotho的表达，减少系统和肾脏的氧化应激表达，减少线粒体损伤。吡格列酮能够通过蛋白激酶C-β通路调节p66Shc磷酸化，因此能够整合多种信号通路，影响线粒体功能和活性。这些结果表明PPAR-r受体激动剂可能通过提高线粒体功能保护年龄相关的肾功能损伤。

医学岛推荐原文：
The PPARγ Agonist Pioglitazone Ameliorates Aging-Related Progressive Renal Injury

Pioglitazone, a peroxisome proliferator-activated receptor (PPARγ) agonist and member of the thiazolidinedione (TZDs) class of antidiabetic drugs, improves insulin-mediated glucose uptake into skeletal muscle without increasing endogenous insulin secretion and improves dyslipidemia. PPARγ agonist was also effective in the treatment of non–insulin-dependent diabetes mellitus. However, PPARγ also has nonmetabolic effects, such as regulating cell cycle, inhibiting inflammation, and modulating cytokine production. Our previous studies have shown that PPARγ agonist ameliorates nondiabetic glomerulosclerosis. Recently, a protective effect of pioglitazone against oxidative stress in liver and kidney of diabetic rabbits was reported.

Long-term exposure to pioglitazone improved mitochondrial function. Of note, mitochondria produce more than 90% of reactive oxygen species (ROS) after related injury. More importantly, one study showed that the Pro/Ala PPARγ gene polymorphism, which is related to PPARγ activity and insulin sensitivity, is also associated with human longevity. However, there is little information about PPAR modulation during aging. Because expression of PPARγ is reduced during aging and TZDs have many beneficial effects on aging-related molecules, we hypothesized that pioglitazone could protect against aging-related renal injury. Our results indeed show that activation of PPARγ is protective against aging-related renal injury. Mechanisms of this effect are associated with increased klotho and reduced mitochondrial oxidation, which is signaled by increased p66Shc phosphorylation through the protein kinase C-β pathway.

Here, we found that the PPAR-γ agonist pioglitazone protected against renal injury in aging; it reduced proteinuria, improved GFR, decreased sclerosis, and alleviated cell senescence. Increased local expression of PPAR-γ paralleled these changes. Underlying mechanisms included increased expression of klotho, decreased systemic and renal oxidative stress, and decreased mitochondrial injury. Pioglitazone also regulated p66Shc phosphorylation, which integrates many signaling pathways that affect mitochondrial function and longevity, by reducing protein kinase C-β. These results suggest that PPAR-γ agonists may benefit aging-related renal injury by improving mitochondrial function.

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