Renin-Angiotensin System

Afferent Macula Densa JG Apparatus Efferent

Factors Affecting Renin Release Increased By Decreased By Na+, water retention BP Activation of AT1 receptors (short loop negative feed back) Arterial BP BP in Glomerular Vessels Loss of Na+, water Sympathetic activity Renin Release

Renin- synthesized, stored and released by exocytosis into renal artery circulation by JG cells Both renin and prorenin are stored in the JG cells Prorenin is converted to renin by proteolytic enzymes- proconvertase I or cathepsin B Concentration of prorenin is about 10 times higher than renin in circulating blood Renin converts angiotensinogen to angiotensin I which is then converted to angiotensin II by Angiotensin Converting Enzyme (ACE) Angiotensin II is the active form of the enzyme

Control of Renin Secretion Macula densa pathway Intrarenal baroreceptor pathway -receptor pathway

Macula densa pathway Specialized columnar epithelial cells in thick ascending limb of the nephron Lies between the afferent and efferent arterioles adjacent to the JG apparatus Reabsorption of NaCl occurs by macula densa cells Changes in NaCl reabsorption modify renin release from the JG cells Increase in NaCl flux causes inhibition of renin release while decrease causes increased renin release ATP, adenosine & PG modulate this pathway

Macula densa- control of renin release AngII ATP Na+ 2Cl- K+ Na+-K+-2Cl- symporter + Na+ -ve Feed back K+ AT1 NE release 1 ADP P2Y — Tubular End (Gq-PLC-IP3 - Ca2+ Adenosine PG nNOS A1 (-) (+) Renin Release Adenosine Receptor NO COX-2 PG Macula densa JG Cell

In macula densa, regulation is mainly by concentration of Cl- concentration rather than Na+ concentration Concentration of Na+ in tubular lumen is usually higher than required for saturating the symporter due to which changes in levels of Na+ do not have much effect on macula densa Cl- concentrations required for saturation of the symporter are high due to which changes in its concentration mainly effect macula densa mediated renin release

Renin release control: mechanism II- intrarenal baroreceptor pathway  in BP or renal perfusion pressure in preglomerular vessels inhibits renin release and vice versa May be mediated by stretch receptors in arterial walls or/and by PG synthesis Mechanism III: via 1 receptors on JG cells

Increased renin secretion enhances formation of angiotensin II which is responsible for short loop negative feed back Other factors in negative feed back: Activating high pressure baroreceptors and thereby reducing renal sympathetic tone- k/a long loop negative feed back Increasing pressure in the preglomerular vessels Reducing NaCl reabsorption from the proximal tubule (pressure natriuresis) thereby reducing delivery of NaCl to macula densa which reduces renin release

Physiological factors modifying renin release: Systemic blood pressure Dietary salt intake Pharmacological agents- NSAIDs- inhibit PG synthesis   renin release Loop diuretics decrease BP and increase NaCl reabsorption causing increased renin release ACE inhibitors, ARBs, renin inhibitors Centrally acting sympatholytic agents and -blockers decrease renin secretion by reducing -receptor activation

ACE It is a glycoprotein It is nonspecific enzyme that catalyzes diverse amino acids It is identical to Kinase II that inactivates bradykinin and other potent vasodilator peptides ACE is present in the vascular endothelium which is responsible for rapid conversion of Ang I to Ang II ACE2: present in human body- carboxypeptidase It cleaves one amino acid residue from Ang I to convert it to Ang (1-9) and Ang II to Ang (1-7) Ang (1-7) binds to Mas receptors and elicits vasodilator and non-proliferative responses

ACE2 has 400 fold greater affinity for AngII than AngI ACE2 is not inhibited by standard ACE inhibitors used It has no effect on bradykinin Physiological significance uncertain May act a a counter-regulatory mechanism to oppose effects of ACE It regulates effects of Ang II by converting it to Ang (2-8) also called Ang III Ang IV (3-8) is formed from Ang III Ang I has is less than 1% potent than Ang II

Angiotensinogen is formed in the liver Major site for conversion of Ang I to Ang II is the lung Reason: because it has a large number of capillaries and ACE is present in the endothelial cells of the capillaries Other sites: other blood vessels specially of kidney Angiotensinages are diverse group of enzymes like aminopeptidases, endopeptidases, carboxypeptidases and other peptidases that degrade and inactivate angiotensin They are non-specific enzymes

Local (Tissue) Renin-Angiotensin System Important for its role in hypertrophy, inflammation, remodelling and apoptosis Binding of renin or pro-renin to pro-renin receptors located on cell surface Present in many tissues like brain, pituitary blood vessels, heart, kidney, adrenal glands Extrinsic local RAS: in vascular endothelium of these tissues Intrinsic local RAS: tissues having mRNA expression

Number of enzymes that act as alternative pathway for conversion of angiotensinogen to AngI or directly to AngII Enzymes are: cathepsin, tonin, cathepsin G, chymostatin sensitiveAngII generating enzyme and heart chymase Angiotensin receptors:two types- AT1 and AT2 Most effects of AngII are mediated by AT1 receptors Role of AT22 receptors not well defined May counterbalance many effects of AT1 activation

Functions of RAS Effects of AngII on CVS include: Rapid pressor respone-  peripheral resistance Slow pressor response- via decrease in renal excretion and production of endothelin-1 Vascular and cardiac hypertrophy and remodeling

Rapid pressor response: AT1 receptors are located in the vascular smooth muscle cells Ang II activates these receptors and constricts the precapillary arterioles and to a lesser extent the postcapillary venules It stimulates the Gq-PLC-IP3-Ca2+ pathway Vasoconstriction is maximum in kidneys, lesser in splanchnic. Weak vasoconstrictor action in brain, lung and skeletal muscles

Other contributing factors are: Enhancement of peripheral NE neurotransmission by: Inhibiting reuptake of NE into nerve terminals Enhancing vascular response to NE High concentrations of Ang II stimulate ganglion cells directly CNS Effects: Increase in central sympathetic outflow Attenuation of baroreceptor mediated reductions in sympathetic discharge from brain

Brain contains all components of RAS Brain is affected by both circulating AngII and AngII formed within the brain Action of AngII on brain causes: Increased central sympathetic tone Dipsogenic effect (thirst) Release of catecholamines from adrenal medulla: AngII depolarises the chromaffin cells of adrenal medulla and causes release of adrenaline

Slow Pressor Response: Produced by effect on the kidneys AngII: Reduces urinary excretion of Na+ and water Increases excretion of K+ Stimulates Na+/H+ exchange in proximal tubule due to which Na+, Cl- and bicarbonate reabsorption increases Increases expression of Na+-glucose symporter in proximal tubule Directly stimulates Na+-K+-2Cl- symporter in thick ascending limb

Proximal tubule secretes angiotensinogen and the connecting tubule secretes renin Paracrine tubular RAS? Functions? AngII stimulates zona glomerulosa of adrenal cortex to increase the synthesis and secretion of aldosterone Also auguments its response to other stimuli like ACTH, K+ Aldosterone acts on distal and collecting tubules to cause retention of Na+ and excretion of K+ and H+ Stimulatory effect of AngII on aldosterone secretion depends on plasma concentrations of Na+ and K+

Release of aldosterone is enhanced in cases of hyponatremia or hyperkalemia and vice versa Effect on glomerular filtrate: Constriction of afferent arterioles reduces intraglomerular pressor and tends to reduce GFR Contraction of mesangial cells decreases the capillary surface area within the glomerulous and tends to decrease GFR Constriction of efferent arterioles increases the intraglomerular pressor and tends to increase GFR Normally, GFR is slightly reduced by AngII

Vascular and cardiac hypertrophy and remodeling: Cells involved- vascular smooth muscle cells, cardiac myocytes and fibroblasts Stimulates migration, proliferation and hypertrophy of vascular smooth muscle cells Increases extracellular matrix production by vascular smooth muscle cells Causes hypertrophy of cardiac myocytes Increases extracellular matrix production by cardiac fibroblasts

Effect on heart: Increases cardiac contractility directly by opening of voltage gated Ca2+ channels in cardiac myocyte Increases cardiac rate indirectly by increasing central sympathetic tone Increases adrenal release of catecholamines Facilitates adrenergic neurotransmission Rapid rise in BP causes baroreceptor stimulation- decrease in central sympathetic tone and increased vagal tone Net effect-uncertain

Inhibitors of RAS ACE inhibitors (ACEIs) Angiotensin receptor blockers (ARBs) Direct renin inhibitors (DRIs)