RAAS and PET

Renin-angiotensin or renin-angiotensin-aldosterone system (RAS or RAAS, respectively) regulates [Na+] in plasma, affecting fluid balance and arterial blood pressure. Systemic and myocardial renin-angiotensin system is upregulated in various cardiac diseases (Lautamäki et al., 2014).

At the base of the internal carotid artery the dilated area, carotid sinus, contains baroreceptors, which connect via brain stem to the hypothalamus, affecting the activity of the sympathetic and parasympathetic nervous systems. Baroreceptors are found also in other arteries, including aortic arch. Renal sympathetic tone regulates the release of renin from kidneys, which affects the production of circulating angiotensins, which via angiotensin receptors regulate the production of aldosterone in adrenal glands.

Renin

Renin is an enzyme which produces proangiotensin (angiotensin I) by cleaving this 10 amino acid long peptide from plasma α-2-globulin (angiotensinogen), which is produced by the liver and renal proximal tubule cells.

Renin is produced in the kidneys by juxtaglomerular cells (modified pericytes) in the glomerular capillary. Juxtaglomerular cells can detect changes in the local blood pressure, [Na+] in the filtrate, and are affected by the sympathetic tone. Reduced blood pressure, reduced [Na+] and [Cl-], and increased sympathetic tone, causes juxtaglomerular cells to release more renin.

ACE

On surface of endothelial cells, angiotensin-converting enzyme (ACE) converts proangiotensin (angiotensin I) into angiotensin II. Most of the circulating angiotensin II is produced by ACE in the lungs. ACE also degrades vasodilator bradykinin, substance P, and β-amyloid. ACE is also expressed on the epithelial cells of kidneys, and in the brain. Endothelial cells produce also other vasoconstrictors such as endothelin-1.

ACE activity in kidney and lung can be measured with 4-cis-[18F]fluorocaptopril ([18F]FCAP) (Hwang et al., 1991; Markham et al., 1995; Schuster et al., 1995; Qing et al., 2000).

ACE2

Angiotensin-converting enzyme 2 (ACE2) is found on cell membranes (mACE2) and in soluble form (sACE2). ACE2 is mainly expressed in intestines, proximal tubular cells of the kidneys, gallbladder, and endothelial and muscle cells of the heart. Blood pressure is mainly affected by sACE2, not mACE2. Some viruses can enter cells via mACE2.

Tissue expression of ACE2 may be assessed using [68Ga]NOTA-PEP4 (Parker et al., 2021).

Angiotensins

Angiotensin II

Angiotensin II binds to angiotensin receptors, causing vasoconstriction, release of aldosterone from adrenal glands. Aldosterone increases Na+ reabsorption in the kidneys, which leads to increased blood pressure. In CNS angiotensin II increases production of vasopressin.

The half-life of angiotensin II in circulation is very short, as it is rapidly degraded by angiotensinases in RBCs and vascular beds, but in tissues the half-life can be much longer. Angiotensin II is involved in the regulation of vascular remodelling via angiogenesis and angiolysis.

In kidneys, chronically elevated angiotensin II level leads to medullary microvascular dysfunction and hypoxia, which can be prevented with P2X7R antagonist (Menzies et al., 2015). RAAS is physiologically modulated by changing the expression of angiotensin II type 1 receptors (AT1Rs).

ACE inhibitors and AT1R antagonists (ARBs) are commonly used for treating diabetic nephropathy, hypertonia, and congestive heart failure.

Angiotensin III

Angiotensin III is produced from angiotensin II by glutamyl aminopeptidase A. It increases aldosterone secretion like angiotensin II, but the potential for causing vasoconstriction is lower.

Angiotensin IV

Angiotensin IV binds to the AT4 receptors, and has adrenocortical and vasopressor activity.

Angiotensin receptors

Angiotensin II binds with similar affinity to AT1 and AT2 receptors. AT4Rs are activated by angiotensin IV.

AT1R

The angiotensin II type 1 receptor (AT1R, AGTR1) is found in the heart, vasculature, kidney, adrenal cortex, lungs, and brain. AT1R mediates the main effects of angiotensin II. Activation of AT1Rs leads to reduced renin secretion by the kidneys.

Availability of renal angiotensin II type 1 receptors (AT1Rs) in tissues can be measured in vivo using for example [11C]KR31173 (Mathews et al., 2004; Zober et al., 2006; Xia et al., 2008; Higuchi et al., 2010; Fukushima et al, 2012; Gulaldi et al., 2013; Feng et al., 2015), [11C]L-159884 (Kim et al., 1996; Szabo et al., 1998 and 2001; Owonikoko et al., 2004; Zober et al., 2008), [18F]FPyKYNE-losartan ([18F]fluoropyridine-losartan) (Hachem et al., 2016; Ismail et al., 2016 and 2017; Abreau Diaz et al., 2023), [18F]fluoropyridine-candesartan (Abreau Diaz et al., 2021), 18F-labelled AT1R antagonist irbesartan (Hoffmann et al., 2018), and valsartan derivative [18F]FV45 (Chen et al, 2018).

AT2R

Angiotensin II type 2 receptors (AT2Rs) are mainly expressed in adrenal gland. When activated by angiotensin II, AT2Rs evoke opposite effects to the activation of AT1Rs.

Angiotensin II type 2 receptors (AT2Rs) are also found in the inner membranes of mitochondria, and when activated, increase respiration, membrane potential and ROS production.

AT2R forms heterodimers with relaxin family peptide receptor 1 (RXFP1), which are essential for the antifibrotic effects of relaxin.

Aldosterone

Aldosterone

Aldosterone is secreted from the zona glomerulosa of adrenal cortex in response to angiotensin II, angiotensin III, hyperkalemia, and ACHT. ANP inhibits aldosterone secretion.

Aldosterone binds to mineralocorticoid receptors. In the renal late distal convoluted tubules, connecting tubules, and collecting ducts this leads to activation of basolateral Na+/K+ pumps, which enhances Na+ reabsorption by the epithelial sodium channel.

Aldosterone synthase (hydroxylase cytochrome P450, CYT11B2) is a key enzyme in the biosynthesis of aldosterone (Mendichovszky et al., 2016). Aldosterone synthase specific PET radiopharmaceuticals have been developed, including [18F]CDP2230 and [18F]AldoView, for imaging adrenal masses. [11C]MTO binds to aldosterone synthase and steroid 11β-hydroxylase (which produces corticosterone).


See also:


Literature

Azushima K, Morisawa N, Tamura K, Nishiyama A. Recent research advances in renin-angiotensin-aldosterone system receptors. Curr Hypertens Rep. 2020; 22(3):22. doi: 10.1007/s11906-020-1028-6.

Lautamäki R, Knuuti J, Saraste A. Recent developments in imaging of myocardial angiotensin receptors. Curr Cardiovasc Imaging Rep. 2014; 7: 9245. doi: 10.1007/s12410-013-9245-x.

Navar LG. Physiology: hemodynamics, endothelial function, renin-angiotensin-aldosterone system, sympathetic nervous system. J Am Soc Hypertens. 2014; 8(7): 519-524. doi: 10.1016/j.jash.2014.05.014.

Widlansky ME, Malik MA (2015). Vascular Endothelial Function. In: Lanzer P (eds) PanVascular Medicine. Springer. doi: 10.1007/978-3-642-37078-6_8.



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Updated at: 2023-02-21
Created at: 2015-08-23
Written by: Vesa Oikonen