Liver X receptors α and β regulate renin expression in vivo

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 alpha (LXR alpha) and LXR beta 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 LXR alpha functioned as a cAMP-activated factor, LXR beta was inversely affected by cAMP. In vivo, LXRs colocalized in juxtaglomerular cells, in which LXR alpha was specifically enriched, and interacted with the renin promoter. In mouse models, renin-angiotensin activation was associated with increased binding of LXR alpha to the responsive element. Moreover, acute administration of LXR agonists was followed by upregulation of renin transcription. In LXR alpha(-/-) mice, the elevation of renin triggered by adrenergic stimulation was abolished. Untreated LXR beta(-/-) mice exhibited reduced kidney renin mRNA levels compared with controls. LXR alpha(-/-)LXRP(-/-) mice showed a combined phenotype of lower basal renin and blunted adrenergic response. In conclusion, we show herein that LXR alpha. and LXR beta regulate renin expression in vivo by directly interacting with the renin promoter and that the cAMP/LXR alpha signaling pathway is required for the adrenergic control of the renin-angiotensin system.