Hypoxia-inducible factor-1α (HIF-1α) and autophagy in polycystic kidney disease (PKD)
Hypoxia-inducible factor-1α (HIF-1α) and autophagy in polycystic kidney disease (PKD)
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DOI：
10.1152/ajprenal.00348.2010
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发表时间：
2011-05-01
影响因子：
4.2
通讯作者：
Edelstein, Charles L.
中科院分区：
文献类型：
--
作者：
Belibi, Franck;Zafar, Iram;Edelstein, Charles L.
Belibi F，Zafar I，Ravichandran K，Segvic AB，Jani A，Ljubanovic DG，埃德尔斯坦CL.缺氧诱导因子-1 α（HIF-1 α）和多囊肾病（PKD）中的自噬美国肾脏生理学杂志300：F1235-F1243，2011年。首次发表于2011年1月26日; doi：10.1152/ajprenal.00348.2010.-多囊肾病（PKD）的囊肿扩张导致肾脏局部缺氧，可能激活缺氧诱导因子-1 α（HIF-1 α）。HIF-1 α和自噬是一种程序性细胞修复的形式，由缺氧诱导。目的是确定PKD大鼠和小鼠模型中的HIF-1 α表达和自噬。采用电化学发光法检测HIF-1 α。通过电子显微镜（EM）观察自噬。免疫印迹法检测自噬标志物LC 3和beclin-1。研究了8周龄雄性杂合子（Cy/+）和4周龄纯合子（Cy/Cy）Han：SPRD大鼠、4周龄cpk小鼠和112日龄Pkd 2基因突变的Pkd 2 WS 25/-小鼠。HIF-1 α在巨大的Cy/Cy和cpk肾脏中显著增加，而不是较小的Cy/+和Pkd 2 WS 25/-肾脏。在EM上，在野生型（+/+）、Cy/+和cpk肾中观察到自噬特征：自噬体、线粒体自噬和自溶体。具体而言，自噬体在cpk小鼠的囊肿衬里的管状细胞中的EM上被发现。在Cy/Cy和cpk肾脏中，LC 3-II（自噬体产生的标志物）和beclin（自噬的调节剂）的增加遵循与HIF-1 α相同的增加模式。为了确定HIF-1 α在囊肿形成和/或生长中的作用，Cy/+大鼠、Cy/Cy大鼠和cpk小鼠用HIF-1 α抑制剂2-甲氧基乙烯基吡咯烷酮（2 ME 2）处理。2 ME 2对肾脏体积和囊肿体积密度无明显影响。总之，HIF-1 α在PKD晚期高度表达，并与LC 3-II和beclin-1的增加相关。首次证实PKD肾脏中存在自噬体。抑制HIF-1 α没有治疗效果。
Belibi F, Zafar I, Ravichandran K, Segvic AB, Jani A, Ljubanovic DG, Edelstein CL. Hypoxia-inducible factor-1 alpha (HIF-1 alpha) and autophagy in polycystic kidney disease (PKD). Am J Physiol Renal Physiol 300: F1235-F1243, 2011. First published January 26, 2011; doi:10.1152/ajprenal.00348.2010.-Cyst expansion in polycystic kidney disease (PKD) results in localized hypoxia in the kidney that may activate hypoxia-inducible factor-1 alpha (HIF-1 alpha). HIF-1 alpha and autophagy, a form of programmed cell repair, are induced by hypoxia. The purposes were to determine HIF-1 alpha expression and autophagy in rat and mouse models of PKD. HIF-1 alpha was detected by electrochemiluminescence. Autophagy was visualized by electron microscopy (EM). LC3 and beclin-1, markers of autophagy, were detected by immunoblotting. Eight-week-old male heterozygous (Cy/+) and 4-wk-old homozygous (Cy/Cy) Han:SPRD rats, 4-wk-old cpk mice, and 112-day-old Pkd2WS25/- mice with a mutation in the Pkd2 gene were studied. HIF-1 alpha was significantly increased in massive Cy/Cy and cpk kidneys and not smaller Cy/+ and Pkd2WS25/- kidneys. On EM, features of autophagy were seen in wild-type (+/+), Cy/+, and cpk kidneys: autophagosomes, mitophagy, and autolysosomes. Specifically, autophagosomes were found on EM in the tubular cells lining the cysts in cpk mice. The increase in LC3-II, a marker of autophagosome production and beclin, a regulator of autophagy, in Cy/Cy and cpk kidneys, followed the same pattern of increase as HIF-1 alpha. To determine the role of HIF-1 alpha in cyst formation and/or growth, Cy/+ rats, Cy/Cy rats, and cpk mice were treated with the HIF-1 alpha inhibitor 2-methoxyestradiol (2ME2). 2ME2 had no significant effect on kidney volume or cyst volume density. In summary, HIF-1 alpha is highly expressed in the late stages of PKD and is associated with an increase in LC3-II and beclin-1. The first demonstration of autophagosomes in PKD kidneys is reported. Inhibition of HIF-1 alpha did not have a therapeutic effect.