1. Renin-Angiotensin System

2. Afferent
Macula Densa
JG Apparatus
Efferent

3. 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

4. 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

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

6. 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

7. 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-IP Ca2+
Adenosine PG
nNOS A1
(-) (+)
Renin Release
Adenosine Receptor NO
COX-2 PG
Macula densa JG Cell

8. 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

9. 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

10. 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

11. 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

12. 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

13. 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

14. 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

15. 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

16. 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

17. 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

18. 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

19. 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

20. 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

21. 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

22. 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+

23. 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

24. 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

25. 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

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