Renin-Angiotensin%20System

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Renin-Angiotensin System
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Afferent
Macula Densa
JG Apparatus
Efferent
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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
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• 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

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• Control of Renin Secretion
• Macula densa pathway
• Intrarenal baroreceptor pathway
• ?-receptor pathway

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• 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

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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
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• 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

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• 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

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• 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

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• 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

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• 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

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• 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

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• 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

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• 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

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• 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 receptorstwo 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

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• 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

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• 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

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• 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

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• 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

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• 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

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• 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

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• 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

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• 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

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• 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

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