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.
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
Title and authors | Publication | Year |
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Physiology and Pathophysiology of the Intrarenal Renin-Angiotensin System: An Update
T Yang, C Xu |
Journal of the American Society of Nephrology : JASN | 2017 |
Activation of liver X receptor inhibits OCT2-mediated organic cation transport in renal proximal tubular cells
T Wongwan, S Kittayaruksakul, N Asavapanumas, V Chatsudthipong, S Soodvilai |
Pflügers Archiv - European Journal of Physiology | 2017 |
Transcriptome Analysis of Human Reninomas as an Approach to Understanding Juxtaglomerular Cell BiologyNovelty and Significance
AG Martini, LK Xa, MJ Lacombe, A Blanchet-Cohen, C Mercure, B Haibe-Kains, EC Friesema, AH van Meiracker, KW Gross, M Azizi, P Corvol, G Nguyen, TL Reudelhuber, AH Danser |
Hypertension | 2017 |