TTF-1, a homeodomain-containing transcription factor, participates in the control of body fluid homeostasis by regulating angiotensinogen gene transcription in the rat subfornical organ.
In recent years, it has become increasingly evident that angiotensins synthesized in the brain contribute to regulating body fluid homeostasis. Although angiotensinogen, the unique angiotensin precursor, is produced in the brain, the factors that regulate its gene expression remain unknown. We recently found that TTF-1, a homeodomain-containing transcription factor essential for the development of the fetal diencephalon, is postnatally expressed in discrete areas of the hypothalamus. We now report that the subfornical organ, an important site of angiotensinogen synthesis, is an extra-hypothalamic site of TTF-1 expression. Double in situ hybridization histochemistry demonstrated the presence of TTF-1 mRNA in angiotensinogen-producing cells of the rat subfornical organ. RNase protection assays showed that TTF-1 and angiotensinogen mRNA levels are simultaneously increased in the subfornical organ by water deprivation. The angiotensinogen promoter contains seven presumptive TTF-1 binding motifs, four of which are recognized by the TTF-1 homeodomain. In the C6 glioma cell line, TTF-1 transactivates the angiotensinogen promoter in a dose-dependent manner. This transactivation is abolished by deletion of the TTF-1 binding motif at -125. Intracranial administration of an antisense TTF-1 oligodeoxynucleotide decreased angiotensinogen mRNA in the subfornical organ and dramatically reduced the animal's water intake while increasing urine excretion. Moreover, plasma arginine vasopressin content was decreased by the same treatment. These results demonstrate a novel role for TTF-1 in the regulation of body fluid homeostasis, exerted via the transactivational control of angiotensinogen synthesis in the subfornical organ.
Department of Biological Sciences, College of Natural Sciences, University of Ulsan, Ulsan 680-749, South Korea.
Young June
YJ
Son
Min Kyu
MK
Hur
Byung Jun
BJ
Ryu
Sang Kyu
SK
Park
Giuseppe
G
Damante
Angela Valentina
AV
D'Elia
Maria E
ME
Costa
Sergio R
SR
Ojeda
Byung Ju
BJ
Lee
D000808:Angiotensinogen / Q000235:genetics*; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D001826:Body Fluids / Q000378:metabolism*; D004247:DNA / Q000235:genetics / Q000378:metabolism; D004231:Diuresis; D004326:Drinking; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism*; D006706:Homeostasis; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008297:Male; D008969:Molecular Sequence Data; D009474:Neurons / Q000378:metabolism; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D020319:Oligodeoxyribonucleotides, Antisense / Q000235:genetics / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013356:Subfornical Organ / Q000166:cytology / Q000378:metabolism*; D000074482:Thyroid Nuclear Factor 1; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D014158:Transcription, Genetic; D014868:Water Deprivation / Q000502:physiology
D018398:Homeodomain Proteins; C000614416:Nkx2-1 protein, rat; D009687:Nuclear Proteins; D020319:Oligodeoxyribonucleotides, Antisense; D012333:RNA, Messenger; D000074482:Thyroid Nuclear Factor 1; D014157:Transcription Factors; D000808:Angiotensinogen; D004247:DNA