Activation of liver X receptor-α reduces activation of the renal and cardiac renin–angiotensin–aldosterone system

Abstract

Liver X receptor (LXR)-α is a pivotal player in reverse cholesterol metabolism. Recently, LXR-α was implicated as an immediate regulator of renin expression in a cAMP-responsive manner. To determine whether long-term LXR-α 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-α-deficient (LXR-α−/−) 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 AT1R 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 AT1R were mostly absent in mice deficient for LXR-α, suggesting that these effects are importantly conferred through LXR-α. In conclusion, LXR-α activation blunts ISO-induced increases in mRNA expression of renin, AT1R and ACE in the heart and kidney. These findings suggest a role for LXR-α in RAAS regulation.