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This Article Full Text Full Text (PDF) All Versions of this Article: 289/6/R1763    most recent 00435.2005v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (6) Citing Articles via Google Scholar Google Scholar Articles by Sherrod, M. Articles by Sigmund, C. D. Search for Related Content PubMed PubMed Citation Articles by Sherrod, M. Articles by Sigmund, C. D.

NEUROHUMORAL CONTROL OF CARDIOVASCULAR FUNCTION

Glial-specific ablation of angiotensinogen lowers arterial pressure in renin and angiotensinogen transgenic mice

¹Genetics Graduate Program, ²Department of Internal Medicine, ³Molecular Biology Graduate Program, ⁴Department of Anatomy and Cell Biology, ⁵Department of Physiology & Biophysics, Roy J. and Lucille A. Carver College of Medicine, The University of Iowa, Iowa City, Iowa

Submitted 21 June 2005 ; accepted in final form 9 August 2005

Angiotensinogen (AGT) is mainly expressed in glial cells in close proximity to renin-expressing neurons in the brain. We previously reported that glial-specific overexpression of ANG II results in mild hypertension. Here, we tested the hypothesis that glial-derived AGT plays an important role in blood pressure regulation in hypertensive mice carrying human renin (hREN) and human AGT transgenes under the control of their own endogenous promoters. To perform a glial-specific deletion of AGT, we used an AGT transgene containing loxP sites (hAGT^flox), so the gene can be permanently ablated in the presence of cre-recombinase expression, driven by the glial fibrillary acidic protein (GFAP) promoter. Triple transgenic mice (RAC) containing a: 1) systemically expressed hREN transgene, 2) systemically expressed hAGT^flox transgene, and 3) GFAP-cre-recombinase were generated and compared with double transgenic mice (RA) lacking cre-recombinase. Liver and kidney hAGT mRNA levels were unaltered in RAC and RA mice, as was the level of hAGT in the systemic circulation, consistent with the absence of cre-recombinase expression in those tissues. Whereas hAGT mRNA was present in the brain of RA mice (lacking cre-recombinase), it was absent from the brain of RAC mice expressing cre-recombinase, confirming brain-specific elimination of AGT. Immunohistochemistry revealed a loss of AGT immunostaining glial cells throughout the brain in RAC mice. Arterial pressure measured by radiotelemetry was significantly lower in RAC than RA mice and unchanged from nontransgenic control mice. These data suggest that there is a major contribution of glial-AGT to the hypertensive state in mice carrying systemically expressed hREN and hAGT genes and confirm the importance of a glial source of ANG II substrate in the brain.

renin-angiotensin system; glia; brain; hypertension

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