The renin-angiotensin system (RAS) is a multi-organ system of proteins and receptors that is regulated by hormones and cytokines to control a number of mechanisms associated with fluid balance and vasoconstriction. There are local systems, where the Ang II produced in that tissue binds in that tissue for its specific functions, and a circulating system. Most of Ang II's precursor, angiotensinogen, is produced in the liver. The RAS is present in vascular smooth muscle cells, the heart, kidneys, adrenals, liver, fat tissue (adipocytes), and brain.
Angiotensin II Functions
For more than 50 years, it was known that Ang II was vasoactive - that Ang II stimulated vascular smooth muscle cells. Binding to the type 1 receptor results in vasoconstriction; binding to the type 2 receptor results in vasorelaxation. These alterations in the blood vessel size are the result of a signaling cascade initiated by the conformational change of the Ang II receptor upon binding to Ang II, which allows it to act as a scaffold for tyrosine kinase activation.
However, other functions have been found for the RAS in recent years. These functions include stimulation of the growth and differentiation of vascular smooth muscle cells, cardiac myocytes, and cardiac fibroblasts; inducing the expression of inflammation mediators; increasing the sympathetic release of noradrenalin; and stimulating the signal transducers and activators of transcription (STAT) pathway.
Tissue Specific Actions of Ang II
Depending on the tissue, Ang II's signaling cascades may have different end results as the specific responses of certain cells to the tyrosine kinase activity will depend on the cells' own function. For example, in vascular smooth muscle, Ang II induces vasoconstriction, particularly in the kidneys, but to a lesser extent in the brain, lungs, and skeletal muscle. But in adrenal zona glomerulosa cells it elicits the secretion of aldosterone, and in adrenergic nerve endings Ang II facilitates norepinephrine release. Angiotensin II also affects the kidney by modulating glomerular filtration, facilitating sodium retention by modulating sodium transports, and regulating renal cell growth and differentiation.
The RAS In Cardiovascular Disease
Angiotensin II has been found to induce the rapid formation of reactive oxygen species (ROS) in smooth muscle cells, and the Ang II type 1 receptor has been implicated in the development of ROS and the subsequent development of atherosclerosis. Atherosclerosis is a hardening of the arteries due to cholesterol-containing plaques building up along the interior of the vessels. Reactive oxygen species are known to contribute to the development, and potentially the rupture, of these plaques. The potential consequences of plaque rupture are stroke, heart attack, and death.
References
Berk. Angiotensin II signal transduction in vascular smooth muscle: pathways activated by specific tyrosine kinases. J Am Soc Nephrol 10: S62-S68, 1999.
Inagami. Molecular biology and signaling of angiotensin receptors: an overview. J Am Soc Nephrol 10: S2-S7, 1999.
Kaschina and Unger. Angiotensin AT1/AT2 receptors: regulation, signalling, and function. Blood Pressure 12: 70-88, 2003.
Viedt et al. Differential activation of mitogen-activated protein kinases in smooth muscle cells by angiotensin II. Thromb Vasc Biol 20: 940-948, 2000.
Yin, Yan, and Berk. Angiotensin II singaling pathways mediated by tyrosine kinases. Int J Biochem Cell Biol 35: 780-783, 2003.
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