Glial-specific ablation of angiotensinogen lowers arterial pressure in renin and angiotensinogen transgenic mice.
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.
Sherrod
Mikhiela
M
Genetics Graduate Program, Roy J. and Lucille A. Carver College of Medicine, Univ. of Iowa, Iowa City, Iowa 52242, USA.
Davis
Deborah R
DR
Zhou
Xizhou
X
Cassell
Martin D
MD
Sigmund
Curt D
CD
D000804:Angiotensin II / Q000172:deficiency*; D000808:Angiotensinogen / Q000172:deficiency* / Q000235:genetics; D000818:Animals; D017704:Baroreflex / Q000502:physiology; D001794:Blood Pressure / Q000502:physiology*; D001921:Brain / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D009457:Neuroglia / Q000502:physiology*; D012083:Renin / Q000235:genetics / Q000378:metabolism*; D012084:Renin-Angiotensin System / Q000502:physiology
D000808:Angiotensinogen; D000804:Angiotensin II; D012083:Renin