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Angiotensin II Receptors AT1 and AT2: New Mechanisms of Signaling And Antagonistic Effects of AT1 and AT2

  • Chapter
Angiotensin II Receptor Blockade Physiological and Clinical Implications

Part of the book series: Progress in Experimental Cardiology ((PREC,volume 2))

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Summary

A series of pharmaceutical successes in the treatment of not only essential hypertension but also vascular hypertrophic and hyperplastic diseases, congestive heart failure, and renal degenerative diseases, with angiotensin-converting enzyme inhibitors and angiotensin (Ang) II receptor antagonists indicates that angiotensin may play a pivotal role in the genesis and maintenance of high blood pressure and resultant stroke, atherosclerosis, and heart and kidney diseases. There is more than one form of Ang II receptors. Using expression cloning, we isolated the AT1 cDNA from bovine adrenocortical cells from the kidney of spontaneously hypertensive rats and AT2 cDNA from rat PC12W cells and we showed that it was not the mas oncogene product. Further, we showed that in rodents, AT1 consists of two subtypes, AT1a and AT1b, which share a high degree of sequence homology in their coding regions, although mechanisms of their respective transcriptional control seemed to be different. By computer-assisted modeling and site-directed mutagenesis, we have delineated the docking site of Ang II. AT1a (and AT1b) serves most of the commonly recognized actions of Ang II. In addition, this G protein-coupled receptor (GPCR) also activates a tyrosine kinase mechanism that may be an underlying cause of Ang II-mediated hypertrophic and hyperplastic changes of cardiovascular tissues. In the vascular system, the phospholipase C (PLC) activated by Ang II seems to be PLC-β rather than PLC-γ1.

Interestingly, we found that Gq-activated PLC-β activates p21 ras and mitogen-activated protein kinase (MAPK) in rat vascular smooth muscle cells. The mechanism of the crosstalk between AT1 and the tyrosine kinase system is triggered by Ca2+, but does not involve protein kinase C.

Studies using targeted gene deletion indicated that Ang II is intimately involved in nephrogenesis. Mice lacking angiotensinogen showed an abnormality in the formation of renal papilla, retardation in glomerular maturation, marked hypertrophy of small arteries of the kidney, and tubular dilatation, whereas targeted deletion of the AT1 receptor resulted in small arterial wall hypertrophy. Blood pressure of AT1A-deleted mice was markedly reduced (-45 mmHg).

The role and mechanism of action of AT2 was not clear. We have recently produced AT2 gene null mice and AT1a knockout mice by targeted gene deletion. AT2-deleted mice had a higher blood pressure, whereas AT1-deleted mice showed lower blood pressure. Deletion of the AT2 gene also showed reduced exploratory activity. The most conspicuous action of the AT2 receptor is seen in its salt-retaining action in the renal tubule. Under a constant renal blood flow condition an AT2 antagonist markedly increased the urine volume and concomitant natriuresis. These effects are completely abolished in AT2 deleted mice. The molecular and cell biological studies of the angiotensin receptors are needed.

Despite the complexity and often mutually antagonistic actions of AT1 and AT2, Ang II, working through AT1 and AT2 of the kidney work in the same direction to retain salt and water. These observations, as well as the effects of Ang II, indicate that the most fundamental role of Ang II is its role in the development of the salt-retaining organ, the kidney, and Ang II is uniquely related to the kidney in that both AT1 and AT2 receptors work for the retention of salt.

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Authors and Affiliations

  1. Vanderbilt University School of Medicine, Nashville, TN, USA

    Tadashi Inagami, Satoru Eguchi, Satoshi Tsuzuki & Toshihiro Ichiki

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  1. Tadashi Inagami
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  2. Satoru Eguchi
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  4. Toshihiro Ichiki
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Editors and Affiliations

  1. Institute of Cardiovascular Sciences St. Boniface General Hospital Research Centre Faculty of Medicine, University of Manitoba, Winnipeg, Canada

    Naranjan S. Dhalla Ph.D., M.D. (Hon.) (Distinguished Professor and Director MRC Group in Experimental Cardiology), Peter Zahradka Ph.D. (Associate Professor), Ian M. C. Dixon Ph.D. (Assistant Professor) & Robert E. Beamish M.D. (Professor Emeritus) (Distinguished Professor and Director MRC Group in Experimental Cardiology),  (Associate Professor),  (Assistant Professor) &  (Professor Emeritus)

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Inagami, T., Eguchi, S., Tsuzuki, S., Ichiki, T. (1998). Angiotensin II Receptors AT1 and AT2: New Mechanisms of Signaling And Antagonistic Effects of AT1 and AT2 . In: Dhalla, N.S., Zahradka, P., Dixon, I.M.C., Beamish, R.E. (eds) Angiotensin II Receptor Blockade Physiological and Clinical Implications. Progress in Experimental Cardiology, vol 2. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-5743-2_11

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  • DOI: https://doi.org/10.1007/978-1-4615-5743-2_11

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