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Diabetes:郑宏庭等找到糖尿病肾病治疗新靶点

在2011年11月号的美国糖尿病学会会刊《糖尿病》杂志上,刊登了第三军医大学新桥医院与美国亚利桑那大学药学院等单位联合完成的一项研究成果,该研究率先在国际上应用西兰花、肉桂中萃取的元素对糖尿病肾病进行干预,获得显著疗效。这一研究成果,为糖尿病肾病的临床治疗找到一个新的靶点。

该文第一作者、第三军医大学新桥医院内分泌科副主任郑宏庭博士与美国亚利桑那大学药学院Donna Zhang课题组合作,通过小鼠体内实验和体外细胞模型的观察发现,从食物西兰花和中药材肉桂中提取的莱菔硫烷与肉桂醛这两种物质,可以减弱常见的糖代谢紊乱症状,改善糖尿病引致的糖代谢紊乱与肾损伤,从而为临床糖尿病肾病的治疗探索了一条新的路径。该研究工作得到了国家自然科学基金的资助。

另据了解,美国糖尿病学会会刊《糖尿病》杂志还配发了由国际著名糖尿病研究学者、澳大利亚Baker IDI心脏糖尿病研究中心Judy B.Haan教授所撰写的专文述评。

Haan教授在这篇述评中指出,糖尿病肾病是糖尿病常见的并发症,也是糖尿病患者死亡的主要原因之一。在美国,糖尿病肾病占终末期肾功能衰竭的首位,约为35%至38%。尽管目前临床依靠强化的代谢控制及其他一些干预措施试图延缓其进展,但随着肾功能无情地衰减,许多患者仍不可避免地步入肾衰阶段,这种现状导致了对新治疗手段的迫切需要。而郑宏庭博士他们的研究有望为糖尿病肾病的治疗提供一条全新的途径。

原文:

Therapeutic  Potential of Nrf2 Activators in Streptozotocin-Induced Diabetic Nephropathy

Hongting Zheng1,2, Samantha A. Whitman1, Wei Wu1,2, Georg T. Wondrak1, Pak K. Wong3, Deyu Fang4 and Donna D. Zhang1?

OBJECTIVE  To determine whether dietary compounds targeting NFE2-related factor 2 (Nrf2) activation can be used to attenuate renal damage and preserve renal function during the course of streptozotocin (STZ)-induced diabetic nephropathy.

RESEARCH  DESIGN AND METHODS Diabetes was induced in Nrf2+/+ and Nrf2?/? mice by STZ injection. Sulforaphane (SF) or cinnamic aldehyde (CA) was administered 2 weeks after STZ injection and metabolic indices and renal structure and function were assessed (18 weeks). Markers of diabetes including blood glucose, insulin, polydipsia, polyuria, and weight loss were measured. Pathological alterations and oxidative damage in glomeruli were also determined. Changes in protein expression of the Nrf2 pathway, as well as transforming growth factor-β1 (TGF-β1), fibronectin (FN), collagen IV, and p21/WAF1Cip1 (p21) were analyzed. The molecular mechanisms of Nrf2-mediated protection were investigated in an in vitro model using human renal mesangial cells (HRMCs).

RESULTS  SF or CA significantly attenuated common metabolic disorder symptoms associated with diabetes in Nrf2+/+ but not in Nrf2?/? mice, indicating SF and CA function through specific activation of the Nrf2 pathway. Furthermore, SF or CA improved renal performance and minimized pathological alterations in the glomerulus of STZ-Nrf2+/+ mice. Nrf2 activation reduced oxidative damage and suppressed the expression of TGF-β1, extracellular matrix proteins and p21 both in vivo and in HRMCs. In addition, Nrf2 activation reverted p21-mediated growth inhibition and hypertrophy of HRMCs under hyperglycemic conditions.

CONCLUSIONS  We provide experimental evidence indicating that dietary compounds targeting Nrf2 activation can be used therapeutically to improve metabolic disorder and relieve renal damage induced by diabetes.


 

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