Liver X receptors α and β regulate renin expression in vivo

Fulvio Morello, Rudolf A. De Boer, Knut R. Steffensen, Massimiliano Gnecchi, Jeffrey W. Chisholm, Frans Boomsma, Leonard M. Anderson, Richard M. Lawn, Jan Åke Gustafsson, Marco Lopez-Ilasaca, Richard E. Pratt, Victor J. Dzau

Research output: Contribution to journalArticle

77 Scopus citations

Abstract

The renin-angiotensin-aldosterone system controls blood pressure and salt-volume homeostasis. Renin, which is the first enzymatic step of the cascade, is critically regulated at the transcriptional level. In the present study, we investigated the role of liver X receptor α (LXRα) and LXRβ in the regulation of renin. In vitro, both LXRs could bind to a noncanonical responsive element in the renin promoter and regulated renin transcription. While LXRα functioned as a cAMP-activated factor, LXRβ was inversely affected by cAMP. In vivo, LXRs colocalized in juxtaglomerular cells, in which LXRα was specifically enriched, and interacted with the renin promoter. In mouse models, renin-angiotensin activation was associated with increased binding of LXRα to the responsive element. Moreover, acute administration of LXR agonists was followed by upregulation of renin transcription. In LXRα-/- mice, the elevation of renin triggered by adrenergic stimulation was abolished. Untreated LXRβ-/- mice exhibited reduced kidney renin mRNA levels compared with controls. LXRα-/-LXRβ-/- mice showed a combined phenotype of lower basal renin and blunted adrenergic response. In conclusion, we show herein that LXRα and LXRβ regulate renin expression in vivo by directly interacting with the renin promoter and that the cAMP/LXRα signaling pathway is required for the adrenergic control of the renin-angiotensin system.

Original languageEnglish (US)
Pages (from-to)1913-1922
Number of pages10
JournalJournal of Clinical Investigation
Volume115
Issue number7
DOIs
StatePublished - Jul 2005

ASJC Scopus subject areas

  • Medicine(all)

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