Vallon Volker, Wyatt Amanda W, Klingel Karin, Huang Dan Yang, Hussain Azeemudeen, Berchtold Susanne, Friedrich Björn, Grahammer Florian, Belaiba Rachida S, Görlach Agnes, Wulff Peer, Daut Jürgen, Dalton Nancy D, Ross John, Flögel Ulrich, Schrader Jürgen, Osswald Hartmut, Kandolf Reinhard, Kuhl Dietmar, Lang Florian
Department of Pharmacology & Toxicology, University of Tübingen, Tübingen, Germany.
J Mol Med (Berl). 2006 May;84(5):396-404. doi: 10.1007/s00109-005-0027-z. Epub 2006 Apr 8.
The mineralocorticoids aldosterone and deoxycorticosterone acetate (DOCA) stimulate renal tubular salt reabsorption, increase salt appetite, induce extracellular volume expansion, and elevate blood pressure. Cardiac effects of mineralocorticoids include stimulation of matrix protein deposition leading to cardiac fibrosis, which is at least partially due to the direct action of the hormones on cardiac cells. The signaling mechanisms mediating mineralocorticoid-induced cardiac fibrosis have so far remained elusive. Mineralocorticoids have been shown to upregulate the serum- and glucocorticoid-inducible kinase 1 (SGK1), which participates in the effects of mineralocorticoids on renal tubular Na+ reabsorption and salt appetite. To explore the involvement of SGK1 in the pathogenesis of mineralocorticoid-induced cardiac fibrosis, SGK1 knockout mice (sgk1-/-) and wild-type littermates (sgk1+/+) were implanted a 21-day-release 50-mg DOCA pellet and supplied with 1% NaCl in drinking water for 18 days. This DOCA/high-salt treatment increased blood pressure in both genotypes but led to significant cardiac fibrosis only in sgk1+/+ but not in sgk1-/- mice. According to real-time polymerase chain reaction and Western blotting, DOCA/high-salt treatment enhanced transcript levels and protein expression of cardiac connective tissue growth factor (CTGF) only in sgk1+/+ but not in sgk1-/- mice. Furthermore, DOCA (10 microM) upregulated CTGF expression and enhanced CTGF promoter activity in lung fibroblasts isolated from sgk1+/+ but not from sgk1-/- mice, an effect involving spironolactone-sensitive mineralocorticoid receptors and activation of nuclear factor-kappaB (NFkappaB). Our results suggest that SGK1 plays a decisive role in mineralocorticoid-induced CTGF expression and cardiac fibrosis.
盐皮质激素醛固酮和醋酸脱氧皮质酮（DOCA）可刺激肾小管对盐的重吸收，增加食欲，导致细胞外液量增加，并使血压升高。盐皮质激素对心脏的作用包括刺激基质蛋白沉积，导致心脏纤维化，这至少部分是由于激素对心脏细胞的直接作用。迄今为止，介导盐皮质激素诱导心脏纤维化的信号机制仍不清楚。盐皮质激素已被证明可上调血清和糖皮质激素诱导激酶1（SGK1），该激酶参与盐皮质激素对肾小管钠重吸收和食欲的影响。为了探究SGK1在盐皮质激素诱导的心脏纤维化发病机制中的作用，将SGK1基因敲除小鼠（sgk1-/-）和野生型同窝小鼠（sgk1+/+）植入50 mg的DOCA缓释微丸21天，并在饮用水中加入1%的氯化钠，持续18天。这种DOCA/高盐处理使两种基因型小鼠的血压均升高，但仅在sgk1+/+小鼠中导致显著的心脏纤维化，而sgk1-/-小鼠未出现。根据实时聚合酶链反应和蛋白质印迹分析，DOCA/高盐处理仅在sgk1+/+小鼠中增强了心脏结缔组织生长因子（CTGF）的转录水平和蛋白表达，而在sgk1-/-小鼠中未增强。此外，DOCA（10 microM）上调了从sgk1+/+小鼠而非sgk1-/-小鼠分离的肺成纤维细胞中CTGF的表达，并增强了CTGF启动子活性，这一效应涉及螺内酯敏感的盐皮质激素受体和核因子-κB（NFκB）的激活。我们的结果表明，SGK1在盐皮质激素诱导的CTGF表达和心脏纤维化中起决定性作用。
