TNF-α mediates increased susceptibility to ischemic AKI in diabetes
TNF-α mediates increased susceptibility to ischemic AKI in diabetes
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DOI：
10.1152/ajprenal.00533.2012
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发表时间：
2013-03-01
影响因子：
4.2
通讯作者：
Reeves, W. Brian
中科院分区：
文献类型：
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作者：
Gao, Guofeng;Zhang, Binzhi;Reeves, W. Brian
[10]高G，张B，Ramesh G，Betterly D，Tadagavadi RK，Wang W，Reeves WB. TNF-α介导糖尿病患者缺血性阿基易感性增加美国肾脏生理学杂志304：F515-F521，2013年。首次发表于2013年1月2日; doi：10.1152/ajprenal.00533.2012.-糖尿病是人类和啮齿类动物发生急性肾损伤（阿基）的危险因素。然而，这种观察的机制基础是未知的。本研究评价了炎症和TNF-α在2型糖尿病（DM）模型中缺血性阿基中的作用。对糖尿病（db/db）和非糖尿病（db/+）同窝仔进行20分钟的双侧肾缺血。非糖尿病小鼠仅出现轻度和短暂的肾功能不全。相反，等效的缺血性损伤在db/db小鼠中引起严重和持续的肾功能不全。在肾缺血之前和之后，在糖尿病小鼠的肾脏中测量TNF-α和Toll样受体4（TLR 4）mRNA的表达; db/db小鼠在缺血之后表现出比db/+更大的TNF-α和TLR 4 mRNA表达增加。此外，缺血后db/db小鼠的TNF-α尿排泄量高于db/+小鼠。为了确定TNF-α在介导糖尿病小鼠对缺血性损伤的易感性增强中的可能作用，向db/db小鼠注射中和性抗小鼠TNF-α抗体或非免疫球蛋白，然后进行20分钟的双侧肾缺血。用TNF-α抗体治疗db/db小鼠提供了针对缺血性损伤的显著保护。这些数据支持糖尿病增加缺血诱导的肾功能不全的易感性的观点。这种增加的易感性来自于涉及TNF-α和可能的TLR 4信号传导的炎症反应的增强。
Gao G, Zhang B, Ramesh G, Betterly D, Tadagavadi RK, Wang W, Reeves WB. TNF-alpha mediates increased susceptibility to ischemic AKI in diabetes. Am J Physiol Renal Physiol 304: F515-F521, 2013. First published January 2, 2013; doi:10.1152/ajprenal.00533.2012.-Diabetes is a risk factor for the development of acute kidney injury (AKI) in humans and rodents. However, the mechanistic basis for this observation is unknown. The present studies evaluated the role of inflammation and TNF-alpha in ischemic AKI in a model of type 2 diabetes mellitus (DM). Diabetic (db/db) and nondiabetic (db/+) littermates were subjected to 20 min of bilateral renal ischemia. The nondiabetic mice developed only mild and transient renal dysfunction. In contrast, the equivalent ischemic insult provoked severe and sustained renal dysfunction in the db/db mice. The expression of TNF-alpha and Toll-like receptor 4 (TLR4) mRNA was measured in the kidneys of diabetic mice before and after renal ischemia; db/db mice exhibited greater increases in TNF-alpha and TLR4 mRNA expression following ischemia than did db/+. In addition, urinary excretion of TNF-alpha after ischemia was higher in db/db mice than in db/+ mice. To determine the possible role of TNF-alpha in mediating the enhanced susceptibility of diabetic mice to ischemic injury, db/db mice were injected with either a neutralizing anti-mouse TNF-alpha antibody or nonimmune globulin and then subjected to 20 min of bilateral renal ischemia. Treatment of the db/db mice with the TNF-alpha antibody provided significant protection against the ischemic injury. These data support the view that diabetes increases the susceptibility to ischemia-induced renal dysfunction. This increased susceptibility derives from a heightened inflammatory response involving TNF-alpha and perhaps TLR4 signaling.