A cAMP and CREB-mediated feed-forward mechanism regulates GSK3β in polycystic kidney disease
A cAMP and CREB-mediated feed-forward mechanism regulates GSK3β in polycystic kidney disease
复制标题
DOI：
10.1093/jmcb/mjw022
复制
发表时间：
2016-12-01
影响因子：
5.5
通讯作者：
Rao, Reena
中科院分区：
文献类型：
--
作者：
Kakade, Vijayakumar R.;Tao, Shixin;Rao, Reena
糖原合成酶激酶3 β（GSK 3 β）是一种丝氨酸/苏氨酸蛋白激酶，通常已知在其活性水平上受到调节。然而，在包括多囊肾病（PKD）在内的一些疾病中，GSK 3 β表达增加并发挥病理生理作用。目前的研究旨在确定PKD中GSK 3 β表达增加的机制及其对疾病进展的意义。在PKD小鼠模型中，肾脏GSK 3 β的增加与肾脏cAMP水平和疾病进展的增加相对应。体内和体外研究表明，GSK 3 β是cAMP反应基因，cAMP水平升高（如PKD中所见）可增加GSK 3 β表达。在正常小鼠中，由缺水诱导的加压素信号增加了GSK 3 β 3 β的表达，而后者在再水化后降低。对GSK 3 β启动子的检查揭示了转录因子cAMP反应元件结合蛋白（CREB）的5个潜在结合位点。CREB被发现与GSK 3 β启动子结合，并且对于cAMP介导的GSK 3 β调节是必需的。重要的是，这种调节被证明是前馈回路的一部分，其中cAMP通过CREB调节GSK 3 β表达，而GSK 3 β反过来正向调节cAMP的产生。GSK 3 β或CREB抑制减少体外经上皮液体分泌和囊肿扩张。因此，在这种破坏性周期的任何点中断可能在治疗上有助于减少PKD的囊肿扩张和保护肾功能。
Glycogen synthase kinase 3 beta (GSK3 beta), a serine/threonine protein kinase, is commonly known to be regulated at the level of its activity. However, in some diseases including polycystic kidney disease (PKD), GSK3 beta expression is increased and plays a pathophysiological role. The current studies aimed to determine the mechanism for the increased GSK3 beta expression in PKD and its significance to disease progression. In mouse models of PKD, increases in renal GSK3 beta corresponded with increases in renal cAMP levels and disease progression. In vivo and in vitro studies revealed that GSK3 beta is a cAMP-responsive gene, and elevated cAMP levels, as seen in PKD, can increase GSK3 beta expression. In normal mice, vasopressin signaling induced by water deprivation increased GSK3 beta 3 beta expression, which decreased following rehydration. Examination of the GSK3 beta promoter revealed five potential binding sites for the transcription factor, cAMP response element binding protein (CREB). CREB was found to bind to GSK3 beta promoter and essential for cAMP-mediated regulation of GSK3 beta. Importantly, this regulation was demonstrated to be part of a feed-forward loop in which cAMP through CREB regulates GSK3 beta expression, and GSK3 beta in turn positively regulates cAMP generation. GSK3 beta or CREB inhibition reduced transepithelial fluid secretion and cyst expansion in vitro. Thus, disruption at any point of this destructive cycle may be therapeutically useful to reduce cyst expansion and preserve renal function in PKD.