Renin-Angiotensin System

Afferent

Efferent

JG Apparatus

Macula Densa

Factors Affecting Renin Release

Renin Release

Increased By Decreased By

Arterial BP

BP in Glomerular Vessels

Loss of Na+, water

Sympathetic activity

•Na+, water retention

BP

•Activation of AT1 receptors (short loop negative feed back)

•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

Na+

2Cl-

K+

Tubular End

Na+

K+

ATP

ADP

Adenosine

A1 (-) (+)

Renin Release

P2Y1

PG

AT1

+

—

nNOS

NO

COX-2 PG

Macula densa- control of renin release

(Gq-PLC-IP3 -

Ca2+

Adenosine Receptor

-ve Feed back

Macula densa JG Cell

Na+-K+-2Cl-

symporter NE release

AngII

•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)