Department of Experimental Cardiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
Lab Invest. 2010 Apr;90(4):630-6. doi: 10.1038/labinvest.2010.7. Epub 2010 Feb 1.
Liver X receptor (LXR)-alpha is a pivotal player in reverse cholesterol metabolism. Recently, LXR-alpha was implicated as an immediate regulator of renin expression in a cAMP-responsive manner. To determine whether long-term LXR-alpha activation affects activation of the renal and cardiac renin-angiotensin-aldosterone system (RAAS), we treated mice with T0901317 (T09, a specific synthetic LXR agonist) in combination with the RAAS inducer isoproterenol (ISO). LXR-alpha-deficient (LXR-alpha(-/-)) and wild-type (WT) C57Bl/6J mice were treated with ISO, T09 or both for 7 days. Low-dose ISO treatment, not associated with an increase in blood pressure, caused an increase in renal renin mRNA, renin protein and ACE protein in WT mice. WT mice treated with both ISO and T09 had decreased renal renin, ACE and AT(1)R mRNA expression compared with mice treated with ISO only. Cardiac ACE mRNA expression was also reduced in the hearts of WT mice treated with ISO and T09 compared with those treated with ISO alone. The transcriptional changes of renin, ACE and AT(1)R were mostly absent in mice deficient for LXR-alpha, suggesting that these effects are importantly conferred through LXR-alpha. In conclusion, LXR-alpha activation blunts ISO-induced increases in mRNA expression of renin, AT(1)R and ACE in the heart and kidney. These findings suggest a role for LXR-alpha in RAAS regulation.
肝 X 受体 (LXR)-α 是胆固醇逆向代谢的关键调节因子。最近，LXR-α 被认为是 cAMP 反应性调节肾素表达的直接调节因子。为了确定长期 LXR-α 激活是否会影响肾脏和心脏肾素-血管紧张素-醛固酮系统 (RAAS) 的激活，我们用 T0901317（T09，一种特定的合成 LXR 激动剂）联合 RAAS 诱导剂异丙肾上腺素（ISO）处理小鼠。用 ISO、T09 或两者联合处理 LXR-α 缺陷型（LXR-α(-/-)）和野生型（WT）C57Bl/6J 小鼠 7 天。低剂量 ISO 处理不会引起血压升高，但会增加 WT 小鼠的肾脏 renin mRNA、肾素蛋白和 ACE 蛋白。与仅用 ISO 处理的小鼠相比，同时用 ISO 和 T09 处理的 WT 小鼠的肾脏 renin、ACE 和 AT(1)R mRNA 表达降低。与仅用 ISO 处理的小鼠相比，用 ISO 和 T09 处理的 WT 小鼠的心脏 ACE mRNA 表达也降低。在缺乏 LXR-α 的小鼠中，肾素、ACE 和 AT(1)R 的转录变化大多缺失，这表明这些作用主要是通过 LXR-α 介导的。总之，LXR-α 激活可减弱 ISO 诱导的心脏和肾脏 renin、AT(1)R 和 ACE mRNA 表达增加。这些发现表明 LXR-α 在 RAAS 调节中起作用。
