Abstract 430: LXR Activation Reduces Expression of Renin, ACE, and Angiotensin Receptor Type 1 in Kidney and Heart
Background: Liver X receptor (LXR)-alpha is a pivotal player in the reverse cholesterol metabolism, which stimulates cholesterol efflux from tissues and which has been implicated as an endogenous anti-atherogenic system. Classical activation of LXR-alpha is induced by oxidized cholesterol, or synthetic agonists such as T0901317 (T09). Recently, LXR-alpha was shown to regulate renin expression in a cAMP-responsive manner. It remains unclear if classical LXR-alpha stimulation has ancillary effects besides lipid regulation. The aim of this study therefore was to investigate if LXR-alpha activation by T09 would affect activation of the renin-angiotensin system (RAS).
Methods: C57Bl/6J mice were treated with either isoproterenol (ISO), the synthetic LXR agonist T09, or both, for 3 and 7 days. Liver, heart, and kidneys were assayed with real-time quantitative RT-PCR analysis for mRNA expression of various elements of the RAS (renin, angiotensin receptor type 1 [AT1R], and angiotensin converting enzyme [ACE]).
Results: cAMP release by ISO treatment caused an increase in renal renin mRNA at 3 days and 7 days, as expected (P<0.01). T09 increased liver mRNA of SREBP1c (P<0.01), a downstream gene of LXR-alpha. T09 alone tended to decrease renin expression, while after 3 and 7 days, the ISO-induced increase of renin mRNA in the kidney was abolished by co-treatment with T09 (P<0.001). 3 days treatment with both ISO and T09 decreased renal ACE expression, compared to control animals (P<0.05). Cardiac ACE expression was also reduced after 7 days of T09 treatment, compared to control mice (P<0.05). 3 days treatment of T09 resulted in decreased mRNA levels of AT1R in the kidney of treated mice compared to control mice.
Conclusions: LXR-alpha activation results in a decrease of mRNA expression of renin, AT1R and ACE in heart and kidney. These findings suggest a role for LXR-alpha in RAS regulation, and salutary effects of LXR agonists may, at least in part, be mediated via the RAS.