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- Title
A novel <em>in vivo</em> mechanism for angiotensin type 1 receptor regulation.
- Authors
Nishimura, Hideki; Taiji Matsusaka; Fogo, Agnes; Kon, Valentina; Ichikawa, Iekuni
- Abstract
This study examined whether a regulatory mechanism exists for the angiotensin II receptor that is compatible with <em>in vivo</em> homeostatic need. Experiments were conducted under two different experimental stresses, (1) deletion of receptor protein and (2) chronic extracellular fluid (ECF) volume depletion. To circumvent potentially dampening intermediary feedback signals <em>in vivo</em>, any feedback gain was completely averted through genetic engineering. The coding exon of angiotensin type 1A (AT1A) receptor gene (<em>Agtr1a</em>) was targeting-replaced with a reporter gene, <em>lacZ</em>, so that the transcription of <em>lacZ</em>, instead of <em>Agtr1a</em>, is driven by the native <em>Agtr1a</em> promoter ECF volume depletion by dietary sodium restriction enhanced <em>Agtr1a</em> gene expression in the <em>adrenal</em> gland of wild-type mice. However, although blood pressure fell in the homozygous targeted mice, <em>Agtr1a</em> gene expression remained unchanged in the adrenal, indicating that <em>adrenal Agtr1a</em> gene expression is regulated entirely through angiotensin receptor-ligand interactions. In the kidney, AT1A mRNA assessed by Northern blotting also did not change in AT1A null-mutated mice with or without sodium restriction. However, tissue examinations for lacZ mRNA and activities indicated that sodium restriction and receptor protein depletion result in dramatic up-regulation of <em>Agtr1a</em> gene expression within the renal arterioles, which can be nullified by an experimental normalization of blood pressure. No such change was observed in wild-type mice. This study demonstrates a presence within the resistance vessel of a blood pressure-sensitive mechanism for AT1 receptor regulation that opposes a down-regulatory influence of the ligand during ECF volume depletion.
- Subjects
GENE expression; BLOOD pressure; BODY fluid pressure; GENETIC engineering; GENETIC transcription; ANGIOTENSINS
- Publication
Kidney International, 1997, Vol 52, Issue 2, p345
- ISSN
0085-2538
- Publication type
Article
- DOI
10.1038/ki.1997.340