Angiotensin Tyrosine Kinase Pathways

Blood pressure is regulated by genetic and environmental factors that act together to maintain fluid and ion balance in the body. When this maintenance fails, disease may follow. Chronically high blood pressure, as occurs with high salt diets, is hypertension, which requires treatment to postpone cardiovascular and renal damage, which result in death. Under normal conditions, the body responds to its needs by keeping the blood pressure within normal limits while maintaining the fluid balance.

The Renin-Angiotensin System

One physiological system involved in the regulation of blood pressure is the renin-angiotensin system (RAS). The RAS s a multi-organ system of proteins and receptors regulated by hormones and cytokines to control a number of mechanisms associated with fluid balance and vasoconstriction. Angiotensin II (Ang II) is the active peptide in the RAS and exerts its effects by binding to its receptor, of which there are four known subtypes, though only two have been shown to be important in adult humans, and one is targeted for anti-hypertensive therapy. There is a circulating RAS in which the peptides act as endocrine hormones, and there are local systems in which Ang II is produced in that tissue and binds the receptor in that tissue for its specific functions. Ang II’s precursor, angiotensinogen, is mainly produced in the liver, and the RAS is present in vascular smooth muscle cells, the heart, kidneys, adrenals, liver, fat tissue (adipocytes), and the brain.

Angiotensin II Effects

The Ang II receptors are membrane proteins, specifically G-proteins. When Ang II binds, the intracellular portion of the receptor changes its conformation and becomes a scaffold for signaling molecules within the cell. The type of signaling and its downstream effects depends on the receptor subtype that is bound.

In the kidney, Ang II affects blood pressure by modulating glomerular filtration and facilitating sodium retention; to retain fluid balance, water is retained with the sodium, increasing blood pressure. In vascular smooth muscle, Ang II induces vasoconstriction by binding the type 1 receptor, which reduces the vessel size, resulting in increased pressure. By binding the type 2 receptor, Ang II induces relaxation, which reduces blood pressure. Angiotensin II also induces the secretion of aldosterone from the adrenal glands via the type 1 receptor. Aldosterone is a hormone involved in sodium and fluid retention.

G-proteins and Tyrosine Kinase Signaling

G-proteins switch between guanine nucleotide diphosphate (GDP) and triphosphate (GTP) as the energy of the phosphate bonds is utilized to activate second messengers, such as inositol 1,4,5-triphosphate (IP3). There are three subunits – alpha (a), beta (b), and gamma (g). There are also stimulatory (s), inhibitory (i), and phospholipase C (PLC) activating (q) types of Ga. It is known that the Gaq and Gbg subunits are involved in Ang II receptor activation of tyrosine kinases.

Tyrosine kinases phosphorylate tyrosine; the effects of this phosphorylation depend on the tissue where it occurs. In vascular smooth muscle cells, an increase in intracellular calcium is evoked by IP3, resulting in the activation of myosin light chain kinase and contraction or the secretion of aldosterone from cells in the adrenal cortex. This action results in both smaller vessels and fluid/sodium retention, increasing blood pressure. G-protein mediated activation of PLC-beta, a well known signal transduction pathway, leads to the hydrolysis of phosphatidylinositol, the formation of IP3, and the accumulation of diacylglycerol (DAG). Protein kinase C (PKC) is activated by DAG, also leading to phosphorylation of proteins involved in vasoconstriction in the kidney.

Other Signaling Pathways of Interest

There are many other pathways that are studied in conjunction with hypertension. It has been reported that the activation of Src kinases is one of the first events in the signal transduction cascade induced by Ang II binding to its receptor. Similar to Gq activation, the activation of Src kinases increases intracellular calcium and activates PKC via the PLC pathway. Map kinase (MAPK) activity is also stimulated by Ang II; in fact, sodium pump (Na+, K+ ATPase activity) regulation involves activation of the PI3K/MAPK signaling pathway.

For More Information:

Berk and Corson. Angiotensin II signal transduction in smooth muscle: role of tyrosine kinases. Circ Res 80: 607-616, 1997.

de Gasparo et al. International Union of Pharmacology. XXIII. The Angiotensin II Receptors. Pharmacol Rev 52: 415-472, 2000.

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.

Rabkin et al. Angiotensin II induces activation of phosphotidylinositol 3-kinase in cardiomyocytes. J hypertens 15: 891-899, 1997

Yin, Yan, and Berk. Angiotensin II singaling pathways mediated by tyrosine kinases. Int J Biochem Cell Biol 35: 780-783, 2003.