Angiotensin II (Ang II) is the main effector molecule for the renin-angiotensin system (RAS). The polypeptide exerts its effects via binding to its receptor. In the case of increased blood pressure, and possible cardiovascular disease associations, the type 1 receptor (AT1R) is of interest.
Angiotensin Receptor Regulation
The regulation of AT1R involves many factors, and alterations in its transcriptional activation have been associated with multiple disease states, including obesity and hypertension. However, most studies investigating the transcriptional regulation of the AT1R gene have been performed in rodents. The rodent and human angiotensin type 1 receptors have different promoter regions (Nawata et al 1995), and it can be assumed that they will have different mechanisms of transcriptional regulation.
The Rodent Angiotensin II Type 1 Receptor
Rodents, both mice and rats, have two AT1 receptors, ATR1a and ATR1b. The difference among the rodent receptors is mainly their tissue distribution (Burson et al 1994). The ATR1a protein is most closely associated with the human type 1 receptor, and it is the receptor expressed in most tissues, including key tissues for blood pressure regulation and obesity.
Mouse Angiotensin Receptor Studies
Agtr1 gene knockout mice have decreased blood pressure (Oliverio et al 1997). Crowley et al (2004) showed that the absence of a single Agtr1a allele in mice results in altered receptor density. This loss in receptor number causes a significant reduction in blood pressure (Ito et al 1995). No compensatory mechanisms were present to overcome the deficiency. Alternatively, the increased expression of ATR1a in transgenic mice has been shown to increase blood pressure in female mice (Le et al 2003).
Importance of AT1R Transcriptional Regulation
It has been suggested that increased receptor number results in increased Ang II binding (Crowley et al 2004). If the rodent genes are any indication, physiological or genetic influences that increase the number of AT1 receptors in human tissues could play a role in hypertension or cardiovascular disease. Because the mouse receptor has a similar tissue distribution as the human receptor, and similar function, a step toward determining if this is true is the use of transgenic mice engineered to express the human gene. The regulation of the gene can then be observed in a living setting to determine how it is regulated.
Original Research
Oliverio, M.I., Best, C.F., Kim, H.S., Arendshorst, W.J., Smithies, O., and Coffman, T.M. Angiotensin II responses in AT1A receptor-deficient mice: a role for AT1B receptors in blood pressure regulation. American Journal of Physiology 272: F515-520, 1997.
Ito, M., Oliverio, M. I., Mannon, P. J., Best, C. F., Maeda, N., Smithies, O., and Coffman, T. M. Regulation of blood pressure by the type 1A angiotensin II receptor gene. Proceedings of the National Academy of Sciences USA 92: 3521-3525, 1995.
Crowley, S. D., Tharaux, P-L., Audoly, L. P., and Coffman, T. M. Exploring type I angiotensin (AT1) receptor functions through gene targeting. Acta Physiologica Scandinavica 181: 561-570, 2004.
Le, T. H., Kim, H. S., Allen, A. M., Spurney, R. F., Smithies, O., and Coffman, T. M. Physiological impact of increased expression of the AT1 angiotensin receptor. Hypertension 42: 507-514, 2003.
Burson, J.M., Aguilera, G., Gross, K.W., and Sigmund, C.D. Differential expression of angiotensin receptor 1A and 1B in mouse. American Journal of Physiology. 267: E260-267, 1994.
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