GSK3beta mediates renal response to vasopressin by modulating adenylate cyclase activity.
GSK3beta mediates renal response to vasopressin by modulating adenylate cyclase activity.
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DOI：
10.1681/asn.2009060672
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发表时间：
2010-03
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影响因子：
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通讯作者：
Reena Rao;Satish Patel;C. Hao;J. Woodgett;Raymond C. Harris
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文献类型：
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作者：
Reena Rao;Satish Patel;C. Hao;J. Woodgett;Raymond C. Harris
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，是包括糖尿病和阿尔茨海默病在内的多种疾病药物发现的关键靶标。由于锂是一种有效的GSK 3 β抑制剂，可导致肾源性尿崩症，因此GSK 3 β可能在调节水平衡方面发挥关键作用。我们开发了肾集合管特异性GSK 3 β基因敲除小鼠，以确定GSK 3 β的缺失是否影响精氨酸加压素依赖性肾水重吸收。虽然在正常条件下只有轻度多尿，敲除小鼠表现出受损的尿浓缩能力，以响应缺水或治疗与加压素类似物。与野生型小鼠相比，敲除小鼠的加压素反应性水通道水通道蛋白2的mRNA、蛋白质和膜定位水平降低。敲除小鼠也表达较低水平的pS256-AQP 2，这是一种对膜运输至关重要的磷酸化形式。cAMP水平，水通道蛋白2表达和运输的主要调节因子，在敲除小鼠中也较低。GSK 3 β基因缺失和GSK 3 β的药理学抑制均降低腺苷酸环化酶活性。总之，GSK 3 β失活或缺失通过调节腺苷酸环化酶活性和cAMP生成减少水通道蛋白2的表达，从而损害肾集合管中对加压素的反应。
Glycogen synthase kinase 3beta (GSK3beta), a serine/threonine protein kinase, is a key target of drug discovery in several diseases, including diabetes and Alzheimer disease. Because lithium, a potent inhibitor of GSK3beta, causes nephrogenic diabetes insipidus, GSK3beta may play a crucial role in regulating water homeostasis. We developed renal collecting duct-specific GSK3beta knockout mice to determine whether deletion of GSK3beta affects arginine vasopressin-dependent renal water reabsorption. Although only mildly polyuric under normal conditions, knockout mice exhibited an impaired urinary concentrating ability in response to water deprivation or treatment with a vasopressin analogue. The knockout mice had reduced levels of mRNA, protein, and membrane localization of the vasopressin-responsive water channel aquaporin 2 compared with wild-type mice. The knockout mice also expressed lower levels of pS256-AQP2, a phosphorylated form crucial for membrane trafficking. Levels of cAMP, a major regulator of aquaporin 2 expression and trafficking, were also lower in the knockout mice. Both GSK3beta gene deletion and pharmacologic inhibition of GSK3beta reduced adenylate cyclase activity. In summary, GSK3beta inactivation or deletion reduces aquaporin 2 expression by modulating adenylate cyclase activity and cAMP generation, thereby impairing responses to vasopressin in the renal collecting duct.