过氧化物酶体增殖物激活受体γ激动剂吡格列酮可改善与衰老相关的进行性肾损伤。
The PPARgamma agonist pioglitazone ameliorates aging-related progressive renal injury.
作者信息
Yang Hai-Chun, Deleuze Sebastien, Zuo Yiqin, Potthoff Sebastian A, Ma Li-Jun, Fogo Agnes B
机构信息
Department of Pathology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
出版信息
J Am Soc Nephrol. 2009 Nov;20(11):2380-8. doi: 10.1681/ASN.2008111138. Epub 2009 Oct 1.
Abstract
Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonists not only improve metabolic abnormalities of diabetes and consequent diabetic nephropathy, but they also protect against nondiabetic chronic kidney disease in experimental models. Here, we found that the PPAR-gamma agonist pioglitazone protected against renal injury in aging; it reduced proteinuria, improved GFR, decreased sclerosis, and alleviated cell senescence. Increased local expression of PPAR-gamma paralleled these changes. Underlying mechanisms included increased expression of klotho, decreased systemic and renal oxidative stress, and decreased mitochondrial injury. Pioglitazone also regulated p66(Shc) phosphorylation, which integrates many signaling pathways that affect mitochondrial function and longevity, by reducing protein kinase C-beta. These results suggest that PPAR-gamma agonists may benefit aging-related renal injury by improving mitochondrial function.
摘要
过氧化物酶体增殖物激活受体γ（PPAR-γ）激动剂不仅能改善糖尿病的代谢异常及随之而来的糖尿病肾病，在实验模型中还能预防非糖尿病慢性肾病。在此，我们发现PPAR-γ激动剂吡格列酮可预防衰老过程中的肾损伤；它能减少蛋白尿、改善肾小球滤过率（GFR）、减轻硬化并缓解细胞衰老。PPAR-γ局部表达的增加与这些变化平行。潜在机制包括klotho表达增加、全身及肾脏氧化应激降低以及线粒体损伤减少。吡格列酮还通过降低蛋白激酶C-β来调节p66（Shc）磷酸化，p66（Shc）整合了许多影响线粒体功能和寿命的信号通路。这些结果表明，PPAR-γ激动剂可能通过改善线粒体功能而有益于与衰老相关的肾损伤。
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