Inducible kidney-specific Sgk1 knockout mice show a salt-losing phenotype
Inducible kidney-specific Sgk1 knockout mice show a salt-losing phenotype
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DOI：
10.1152/ajprenal.00535.2011
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发表时间：
2012-04-01
影响因子：
4.2
通讯作者：
Staub, Olivier
中科院分区：
文献类型：
--
作者：
Faresse, Nourdine;Lagnaz, Dagmara;Staub, Olivier
[10]张文辉，张文辉.可诱导的肾特异性Sgk 1基因敲除小鼠表现出失盐表型。美国肾脏生理学杂志302：F977-F985，2012年。首次发表于2012年2月1日; doi：10.1152/ajprenal.00535.2011。血清和糖皮质激素调节激酶1（Sgk 1）的表达由盐皮质激素诱导，反过来，上调肾上皮Na+通道（ENaC）。Sgk 1的完全失活与低Na+饮食引起的短暂尿Na+消耗相关，而集合管中醛固酮介导的ENaC通道激活未发生变化。由于Sgk 1是普遍表达的，我们的目的是研究肾Sgk 1的作用，并产生了一个可诱导的肾脏特异性敲除（KO）小鼠。我们利用了先前描述的TetOn/CreLoxP系统，其中rtTA在Pax 8启动子的控制下，允许肾小管中floxed Sgk 1等位基因的诱导性失活（Sgk 1fl/fl/Pax 8/LC 1小鼠）。我们发现，在一个标准的Na+饮食，肾脏水和Na+/K+排泄有倾向于更高的强力霉素治疗的Sgk 1基因敲除小鼠与对照组小鼠相比。Sgk 1基因敲除小鼠保留Na+的受损能力在低盐饮食下显著增加，尽管血浆醛固酮水平较高。在低Na+饮食中，Sgk 1 KO小鼠也出现高钾尿和体重减轻。这种表型伴随着收缩压和舒张压的降低。在蛋白质水平上，我们观察到泛素蛋白连接酶Nedd 4 -2的磷酸化减少，Na+-Cl-协同转运蛋白（NCC）的表达减少，ENaC的表达减少。
Faresse N, Lagnaz D, Debonneville A, Ismailji A, Maillard M, Fejes-Toth G, Naray-Fejes-Toth A, Staub O. Inducible kidney-specific Sgk1 knockout mice show a salt-losing phenotype. Am J Physiol Renal Physiol 302: F977-F985, 2012. First published February 1, 2012; doi:10.1152/ajprenal.00535.2011.-The expression of the serum-and glucocorticoid-regulated kinase 1 (Sgk1) is induced by mineralocorticoids and, in turn, upregulates the renal epithelial Na+ channel (ENaC). Total inactivation of Sgk1 has been associated with transient urinary Na+ wasting with a low-Na+ diet, while the aldosterone-mediated ENaC channel activation was unchanged in the collecting duct. Since Sgk1 is ubiquitously expressed, we aimed to study the role of renal Sgk1 and generated an inducible kidney-specific knockout (KO) mouse. We took advantage of the previously described TetOn/CreLoxP system, in which rtTA is under the control of the Pax8 promotor, allowing inducible inactivation of the floxed Sgk1 allele in the renal tubules (Sgk1fl/fl/Pax8/LC1 mice). We found that under a standard Na+ diet, renal water and Na+/K+ excretion had a tendency to be higher in doxycycline-treated Sgk1 KO mice compared with control mice. The impaired ability of Sgk1 KO mice to retain Na+ increased significantly with a low-salt diet despite higher plasma aldosterone levels. On a low-Na+ diet, the Sgk1 KO mice were also hyperkaliuric and lost body weight. This phenotype was accompanied by a decrease in systolic and diastolic blood pressure. At the protein level, we observed a reduction in phosphorylation of the ubiquitin protein-ligase Nedd4-2 and a decrease in the expression of the Na+-Cl--cotransporter (NCC) and to a lesser extent of ENaC.