Morello Fulvio, de Boer Rudolf A, Steffensen Knut R, Gnecchi Massimiliano, Chisholm Jeffrey W, Boomsma Frans, Anderson Leonard M, Lawn Richard M, Gustafsson Jan-Ake, Lopez-Ilasaca Marco, Pratt Richard E, Dzau Victor J
Duke University Medical Center, Durham, NC 27710, USA.
J Clin Invest. 2005 Jul;115(7):1913-22. doi: 10.1172/JCI24594.
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)LXR(beta) 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.
肾素-血管紧张素-醛固酮系统控制血压和盐容量稳态。肾素作为该级联反应的首个酶促步骤，在转录水平受到严格调控。在本研究中，我们探究了肝脏X受体α（LXRα）和LXRβ在肾素调控中的作用。在体外，两种LXR均可与肾素启动子中的非典型反应元件结合并调节肾素转录。LXRα作为一种cAMP激活因子发挥作用，而LXRβ则受到cAMP的反向影响。在体内，LXR在球旁细胞中共定位，其中LXRα特异性富集，并与肾素启动子相互作用。在小鼠模型中，肾素-血管紧张素激活与LXRα与反应元件的结合增加有关。此外，急性给予LXR激动剂后肾素转录上调。在LXRα基因敲除小鼠中，肾上腺素能刺激引发的肾素升高被消除。未经处理的LXRβ基因敲除小鼠与对照组相比，肾脏肾素mRNA水平降低。LXRαLXRβ双基因敲除小鼠表现出基础肾素水平较低和肾上腺素能反应减弱的综合表型。总之，我们在此表明，LXRα和LXRβ通过直接与肾素启动子相互作用在体内调节肾素表达，并且cAMP/LXRα信号通路是肾素-血管紧张素系统肾上腺素能控制所必需的。
