Nuclear receptor LXRalpha is involved in cAMP-mediated human renin gene expression.
The cAMP-signaling pathway plays a crucial role in the regulation of the renin gene, but the mechanism involved remains poorly understood. We have focused our studies of renin gene regulation on the unique cAMP responsive element (huREN/CNRE, -135 to -107) in the human renin promoter. We have cloned a protein that binds to this unique CNRE and demonstrated that this protein is liver X receptor-alpha (LXRalpha), a transcriptional factor of the nuclear receptor family. Transient expression of LXRalpha in human renin-producing Calu-6 cells increased cAMP inducibility of human renin promoter. Similarly, LXRalpha-stably transfected Calu-6 cells exhibited increased cAMP inducibility of renin promoter as well as the endogenous renin gene. Site-directed mutation of huREN/CNRE, which disrupted LXRalpha binding, decreased cAMP-induced transcriptional activity of human renin promoter. Furthermore, we demonstrated that the binding of LXRalpha derived from human juxtaglomerular cells, the main production site of renin in the kidney, to the huREN/CNRE in vivo. These results suggest that LXRalpha plays an important role in the cAMP-mediated regulation of human renin gene transcription by binding to CNRE.
Tamura
Kouichi
K
Department of Medicine II, Yokohama City University School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan. tamukou@med.yokohama-cu.ac.jp
Chen
Yuqing E
YE
Tanaka
Yutaka
Y
Sakai
Masashi
M
Tsurumi
Yuko
Y
Koide
Yuichi
Y
Kihara
Minoru
M
Pratt
Richard E
RE
Horiuchi
Masatsugu
M
Umemura
Satoshi
S
Dzau
Victor J
VJ
D002460:Cell Line; D000242:Cyclic AMP / Q000502:physiology*; D004268:DNA-Binding Proteins; D024202:Electrophoretic Mobility Shift Assay; D005786:Gene Expression Regulation; D006801:Humans; D007546:Isoquinolines / Q000494:pharmacology; D000071518:Liver X Receptors; D016297:Mutagenesis, Site-Directed / Q000235:genetics; D009281:Naphthalenes / Q000494:pharmacology; D057093:Orphan Nuclear Receptors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000502:physiology*; D012083:Renin / Q000235:genetics*; D020218:Response Elements / Q000235:genetics*; D013449:Sulfonamides / Q000494:pharmacology; D014158:Transcription, Genetic
D004268:DNA-Binding Proteins; D007546:Isoquinolines; D000071518:Liver X Receptors; C000605213:NR1H3 protein, human; D009281:Naphthalenes; D057093:Orphan Nuclear Receptors; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D013449:Sulfonamides; D000242:Cyclic AMP; D012083:Renin; C058819:calphostin C; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide