Glycogen synthase kinase-3β promotes cyst expansion in polycystic kidney disease.
Glycogen synthase kinase-3β promotes cyst expansion in polycystic kidney disease.
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DOI：
10.1038/ki.2014.427
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发表时间：
2015-06
影响因子：
19.6
通讯作者：
中科院分区：
文献类型：
--
作者：
多囊肾是一种遗传性疾病，其特征是形成充满液体的肾囊肿。PKD中cAMP水平升高刺激进行性囊肿扩大，涉及细胞增殖和经上皮液体分泌，通常导致终末期肾病。糖原合成酶激酶-3（GSK 3）蛋白激酶家族由GSK 3 α和GSK 3 β同种型组成，并且在多种细胞信号传导途径中起关键作用。我们先前发现，细胞增殖调节因子GSK 3 β对cAMP生成和加压素介导的肾脏尿液浓缩也至关重要。然而，GSK 3 β在PKD发病机制中的作用尚不清楚。我们发现，在PKD小鼠和人的肾脏中，GSK 3 β的表达和活性显著上调，并与囊肿衬里上皮相关。在常染色体隐性或常染色体显性PKD小鼠模型中，肾集合管特异性GSK 3 β基因敲除或药物抑制GSK 3可有效减缓PKD的进展。GSK 3失活抑制cAMP生成和细胞增殖，从而减少囊肿扩张，改善肾功能并延长寿命。GSK 3 β抑制还降低了pERK、c-Myc和Cyclin-D1，它们是囊性上皮细胞增殖中已知的促有丝分裂剂。因此，GSK 3 β在PKD病理生理学中发挥新的功能作用，其抑制可能在治疗上有助于减缓PKD的囊肿扩张和进展。
Polycystic kidney diseases (PKDs) are inherited disorders characterized by the formation of fluid filled renal cysts. Elevated cAMP levels in PKDs stimulate progressive cyst enlargement involving cell proliferation and transepithelial fluid secretion often leading to end stage renal disease. The glycogen synthase kinase-3 (GSK3) family of protein kinases consists of GSK3α and GSK3β isoforms and plays a crucial role in multiple cellular signaling pathways. We previously found that GSK3β, a regulator of cell proliferation, is also crucial for cAMP generation and vasopressin mediated urine concentration by the kidneys. However, the role of GSK3β in the pathogenesis of PKDs is not known. Here we found that GSK3β expression and activity were markedly up-regulated and associated with cyst-lining epithelia in the kidneys of mice and humans with PKD. Renal collecting duct specific gene knockout of GSK3β or pharmacological inhibition of GSK3 effectively slowed the progression of PKD in mouse models of autosomal recessive or autosomal dominant PKD. GSK3 inactivation inhibited cAMP generation and cell proliferation resulting in reduced cyst expansion, improved renal function and extended lifespan. GSK3β inhibition also reduced pERK, c-Myc and Cyclin-D1, known mitogens in proliferation of cystic epithelial cells. Thus, GSK3β plays a novel functional role in PKD pathophysiology and its inhibition may be therapeutically useful to slow cyst expansion and progression of PKD.
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影响因子：
10.5
作者：
Harris PC;Torres VE
通讯作者：
Torres VE
影响因子：
2.9
作者：
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影响因子：
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作者：
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影响因子：
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作者：
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通讯作者：
Harris, Peter C.
DOI：
10.1152/ajprenal.00383.2005
发表时间：
2006-07-01
影响因子：
4.2
作者：
Christensen, Birgitte Monster;Kim, Young-Hee;Nielsen, Soren
通讯作者：
Nielsen, Soren