Hormones - Cytokines - Signaling

Kidney International (1997) 52, 345–355; doi:10.1038/ki.1997.340

A novel in vivo mechanism for angiotensin type 1 receptor regulation

Hideki Nishimura1, Taiji Matsusaka1, Agnes Fogo1, Valentina Kon1 and Iekuni Ichikawa1

1Departments of Pediatrics, Medicine and Pathology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA

Correspondence: Iekuni Ichikawa MD, Division of Pediatric Nephrology, Vanderbilt University Medical Center, MCN C4204, Nashville, Tennessee 37232–2584, USA. E-mail: iekuni.ichikawa@mcmail.vanderbilt.edu

Received 12 December 1996; Revised 26 March 1997; Accepted 27 March 1997.

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Abstract

A novel in vivo mechanism for angiotensin type 1 receptor regulation. This study examined whether a regulatory mechanism exists for the angiotensin II receptor that is compatible with in vivo 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 in vivo, any feedback gain was completely averted through genetic engineering. The coding exon of angiotensin type 1A (ATIA) receptor gene (Agtr1a) was targeting-replaced with a reporter gene, lacZ, so that the transcription of lacZ, instead of Agtr1a, is driven by the native Agtr1a promoter. ECF volume depletion by dietary sodium restriction enhanced Agtr1a gene expression in the adrenal gland of wild-type mice. However, although blood pressure fell in the homozygous targeted mice, Agtr1a gene expression remained unchanged in the adrenal, indicating that adrenal Agtr1a 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 Agtr1a 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 ATI receptor regulation that opposes a down-regulatory influence of the ligand during ECF volume depletion.

Keywords:

angiotensin, gene receptor regulation

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