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The renin–angiotensin system (RAS) participates significantly in the pathophysiology of hypertension, congestive heart failure, myocardial infarction, and diabetic nephropathy.




Angiotensin II (AngII), the most vasoactive angiotensin peptide, participates in blood pressure regulation, aldosterone release, Na+ reabsorption from renal tubules, and electrolyte and fluid homeostasis. AngII is derived from angiotensinogen in two 2 proteolytic steps (Figure 26–1). First, renin, an enzyme released from the juxtaglomerular cells of the kidneys, cleaves the decapeptide angiotensin I (AngI) from the amino terminus of angiotensinogen (renin substrate). Then, angiotensin-converting enzyme (ACE) removes the carboxy-terminal dipeptide of AngI to produce the octapeptide AngII. AngII is an agonist ligand for 2 GPCRs, AT1 and AT2. The RAS includes local (tissue) RAS, alternative pathways for AngII synthesis (ACE-independent), formation of other biologically active angiotensin peptides (AngIII, AngIV, Ang[1–7]), and additional angiotensin-binding receptors (AT1, AT2, AT4, Mas) that participate in cell growth differentiation, hypertrophy, inflammation, fibrosis, and apoptosis.

Figure 26–1

Components of the RAS. The heavy arrows show the classical pathway, and the light arrows indicate alternative pathways. ACE, angiotensin-converting enzyme; Ang, angiotensin; AP, aminopeptidase; E, endopeptidases; IRAP, insulin-regulated aminopeptidases; PCP, prolylcarboxylpeptidase; PRR, (pro)renin receptor. Receptors involved: AT1, AT2, Mas, AT4, and PRR. *Exposure of the active site of renin can also occur nonproteolytically; see text and Figure 26–4.

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RENIN AND THE PRORENIN/RENIN RECEPTOR. Renin is the major determinant of the rate of AngII production. It is synthesized, stored, and secreted by exocytosis into the renal arterial circulation by the granular juxtaglomerular cells (Figure 26–2) located in the walls of the afferent arterioles that enter the glomeruli. Renin is an aspartyl protease that cleaves the bond between residues 10 and 11 at the amino terminus of angiotensinogen to generate AngI. The active form of renin is a large glycoprotein that is synthesized as a preproenzyme and processed to prorenin. Prorenin may be activated in 2 ways: proteolytically, by proconvertase 1 or cathepsin B that remove 43 amino acids (propeptide) from prorenin's amino terminus to uncover the active site of renin (Figure 26–3); and nonproteolytically, when prorenin binds to the prorenin/renin receptor (PRR), resulting in conformational changes that unfold the propeptide and expose the active catalytic site of the enzyme. Both renin and prorenin are stored in the juxtaglomerular cells. The concentration of plasma prorenin is ~10x that of the active enzyme. The t1/2 of circulating renin is ~15 min.

Figure 26–2

Physiological pathways, feedback loops, and pharmacological regulation of the renin-angiotensin system. Schematic portrayal of the three major physiological pathways regulating renin release. See text for details. MD, macula densa; PGI2/PGE2 prostaglandins I2 and E2; NSAIDs, nonsteroidal anti-inflamatory drugs; ...

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