Hussain Azeemudeen, Wyatt Amanda W, Wang Kan, Bhandaru Madhuri, Biswas Raja, Avram Diana, Föller Michael, Rexhepaj Rexhep, Friedrich Björn, Ullrich Susanne, Müller Gerhard, Kuhl Dietmar, Risler Teut, Lang Florian
Department of Physiology, University of Tübingen,Tübingen, Germany.
Kidney Blood Press Res. 2008;31(2):80-6. doi: 10.1159/000119703. Epub 2008 Mar 5.
Angiotensin II has previously been shown to trigger fibrosis, an effect involving connective tissue growth factor (CTGF). The signaling pathways linking angiotensin II to CTGF formation are, however, incompletely understood. A gene highly expressed in fibrosing tissue is the serum- and glucocorticoid-inducible kinase SGK1. The present study explored whether SGK1 is transcriptionally regulated by angiotensin II and participates in the angiotensin II-dependent regulation of CTGF expression. To this end, experiments have been performed in human kidney fibroblasts and mouse lung fibroblasts from gene-targeted mice lacking SGK1 (sgk1-/-) and their wild-type littermates (sgk1+/+). In human renal fibroblasts, SGK1 and CTGF protein expression were enhanced by angiotensin II (10 nM) within 4 h. In sgk1+/+ mouse fibroblasts, SGK1 transcript levels were significantly increased after 4 h of angiotensin II treatment. Angiotensin II stimulated both transcript and protein abundance of CTGF in fibroblasts from sgk1+/+ mice, effects significantly blunted in fibroblasts of sgk1-/- mice. In conclusion, angiotensin II stimulates the expression of SGK1, which is in turn required for the stimulating effect of angiotensin II on the expression of CTGF. Thus, SGK1 presumably contributes to the profibrotic effect of angiotensin II.
此前已有研究表明，血管紧张素II可引发纤维化，这种作用涉及结缔组织生长因子（CTGF）。然而，将血管紧张素II与CTGF形成联系起来的信号通路尚未完全明确。在纤维化组织中高表达的一个基因是血清和糖皮质激素诱导激酶SGK1。本研究探讨了SGK1是否受血管紧张素II的转录调控，并参与血管紧张素II依赖的CTGF表达调控。为此，我们使用了来自缺乏SGK1的基因敲除小鼠（sgk1-/-）及其野生型同窝小鼠（sgk1+/+）的人肾成纤维细胞和小鼠肺成纤维细胞进行实验。在人肾成纤维细胞中，血管紧张素II（10 nM）在4小时内可增强SGK1和CTGF蛋白的表达。在sgk1+/+小鼠成纤维细胞中，血管紧张素II处理4小时后，SGK1转录水平显著增加。血管紧张素II可刺激sgk1+/+小鼠成纤维细胞中CTGF的转录和蛋白丰度，而在sgk1-/-小鼠成纤维细胞中，这种作用明显减弱。总之，血管紧张素II可刺激SGK1的表达，而SGK1反过来又是血管紧张素II刺激CTGF表达所必需的。因此，SGK1可能促成了血管紧张素II的促纤维化作用。
