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.
Access optionsAccess options
Subscribe to Journal
Get full journal access for 1 year
only $36.75 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Tontonoz P, Mangelsdorf DJ . Liver X receptor signaling pathways in cardiovascular disease. Mol Endocrinol 2003;17:985–993.
Peet DJ, Turley SD, Ma W, et al. Cholesterol and bile acid metabolism are impaired in mice lacking the nuclear oxysterol receptor LXR alpha. Cell 1998;93:693–704.
Venkateswaran A, Laffitte BA, Joseph SB, et al. Control of cellular cholesterol efflux by the nuclear oxysterol receptor LXR alpha. Proc Natl Acad Sci USA 2000;97:12097–12102.
Willy PJ, Umesono K, Ong ES, et al. LXR, a nuclear receptor that defines a distinct retinoid response pathway. Genes Dev 1995;9:1033–1045.
Peet DJ, Janowski BA, Mangelsdorf DJ . The LXRs: a new class of oxysterol receptors. Curr Opin Genet Dev 1998;8:571–575.
Chen M, Beaven S, Tontonoz P . Identification and characterization of two alternatively spliced transcript variants of human liver X receptor alpha. J Lipid Res 2005;46:2570–2579.
Morello F, de Boer RA, Steffensen KR, et al. Liver X receptors alpha and beta regulate renin expression in vivo. J Clin Invest 2005;115:1913–1922.
Persson PB, Skalweit A, Mrowka R, et al. Control of renin synthesis. Am J Physiol Regul Integr Comp Physiol 2003;285:R491–R497.
Leik CE, Carson NL, Hennan JK, et al. GW3965, a synthetic liver X receptor (LXR) agonist, reduces angiotensin II-mediated pressor responses in Sprague-Dawley rats. Br J Pharmacol 2007;151:450–456.
van der Veen JN, Havinga R, Bloks VW, et al. Cholesterol feeding strongly reduces hepatic VLDL-triglyceride production in mice lacking the liver X receptor alpha. J Lipid Res 2007;48:337–347.
Schultz JR, Tu H, Luk A, et al. Role of LXRs in control of lipogenesis. Genes Dev 2000;14:2831–2838.
Tamura K, Chen YE, Horiuchi M, et al. LXRalpha functions as a cAMP-responsive transcriptional regulator of gene expression. Proc Natl Acad Sci USA 2000;97:8513–8518.
Kuipers I, van der Harst P, Navis G, et al. Nuclear hormone receptors as regulators of the renin-angiotensin-aldosterone system. Hypertension 2008;51:1442–1448.
Elton TS, Martin MM . Angiotensin II type 1 receptor gene regulation: transcriptional and posttranscriptional mechanisms. Hypertension 2007;49:953–961.
Imayama I, Ichiki T, Patton D, et al. Liver X receptor activator downregulates angiotensin II type 1 receptor expression through dephosphorylation of Sp1. Hypertension 2008;51:1631–1636.
This study was supported by the Netherlands Heart Foundation (Grant nos 2004T004 and 2007T046). We thank Dr Inagami for providing the renin antibody.
The authors declare no conflict of interest.
About this article
KAGAKU TO SEIBUTSU (2018)
Scientific Reports (2018)
Journal of the American Society of Nephrology (2017)
Doxorubicin enhances oxysterol levels resulting in a LXR-mediated upregulation of cardiac cholesterol transporters
Biochemical Pharmacology (2017)
Pirfenidone controls the feedback loop of the AT1R/p38 MAPK/renin-angiotensin system axis by regulating liver X receptor-α in myocardial infarction-induced cardiac fibrosis
Scientific Reports (2017)