Glia- and neuron-specific expression of the renin-angiotensin system in brain alters blood pressure, water intake, and salt preference.
The purpose of this study is to examine the regulation of blood pressure and fluid and electrolyte homeostasis in mice overexpressing angiotensin II (Ang-II) in the brain and to determine whether there are significant physiologic differences in Ang-II production in neurons or glia. Therefore, we generated and characterized transgenic mice overexpressing human renin (hREN) under the control of the glial fibrillary acidic protein (GFAP) promoter (GFAP-hREN) and synapsin-I promoter (SYN-hREN) and bred them with mice expressing human angiotensinogen (hAGT) under the control of the same promoters (GFAP-hAGT and SYN-hAGT). Both GFAP-hREN and SYN-hREN mice exhibited the highest hREN mRNA expression in the brain and had undetectable levels of hREN protein in the systemic circulation. In the brain of GFAP-hREN and SYN-hREN mice, hREN protein was observed almost exclusively in astrocytes and neurons, respectively. Transgenic mice overexpressing both hREN and hAGT transgenes in either glia or neurons were moderately hypertensive. In the glia-targeted mice, blood pressure could be corrected by intracerebroventricular injection of the Ang-II type 1 receptor antagonist losartan, and intravenous injection of a ganglion blocking agent, but not an arginine vasopressin V1 receptor antagonist, lowered blood pressure. These data suggest that stimulation of Ang-II type 1 receptors in the brain by Ang-II derived from local synthesis of renin and angiotensinogen can cause an elevation in blood pressure via a mechanism involving enhanced sympathetic outflow. Glia- and neuron-targeted mice also exhibited an increase in drinking volume and salt preference, suggesting that chronic overexpression of renin and angiotensinogen locally in the brain can result in hypertension and alterations in fluid homeostasis.
Morimoto
Satoshi
S
Department of Internal Medicine and Physiology & Biophysics, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242, USA.
Cassell
Martin D
MD
Sigmund
Curt D
CD
D000818:Animals; D001794:Blood Pressure; D001921:Brain / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D049452:Green Fluorescent Proteins; D006973:Hypertension; D007150:Immunohistochemistry; D019808:Losartan / Q000494:pharmacology; D008164:Luminescent Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009457:Neuroglia / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D012084:Renin-Angiotensin System / Q000502:physiology*; D012492:Salts / Q000494:pharmacology; D019076:Transgenes; D014867:Water / Q000378:metabolism*
D018076:DNA, Complementary; D008164:Luminescent Proteins; D012333:RNA, Messenger; D012492:Salts; D014867:Water; D049452:Green Fluorescent Proteins; D019808:Losartan