Renin-angiotensin system
[Ref: WG21:p458-p463]
Basics
Renin
Size
- Preprorenin - 406 amino acid residues
- Prorenin - 383 amino acid residues
- Renin - 340 amino acid residues
Other info
- Halflife in circulation: < 80 minutes
- Only known function: converts angiotensinogen to angiotensin I
Angiotensinogen
- In the alpha2-globulin fraction of the plasma
- Contains 453 amino acids residues and 13% carbohydrate
Factors affecting circulation level
Circulating level is increased by
- Glucocorticoids
- Thyroid hormones
- Oestrogens
- Some cytokines
- Angiotensin II
Angiotensin-converting enzyme (ACE)
- Found in endothelial cells
- Most conversion happens as blood goes through lung.
- Some conversion occurs in kidney
Structure
- Dipeptidyl-carboxypeptidase
- Transmembrane
- Two extracelluar catalytic sites, each of which binds a zinc ion
Function of ACE
- Converts angiotensin I to angiotensin II
- Inactivates bradykinin
Angiotensins
Structure
Angiotensin I - decapeptide (10 amino acids)
Angiotensin II - 8 amino acid peptide
Angiotensin III - 7 amino acid peptide
Functions
Angiotensin I
- Precursor of angiotensin II.
- No other known functions
Angiotensin III
- 40% of the pressor activity of angiotensin II
- 100% of the aldosterone-stimulating activity of angiotensin II
Angiotensin II
Metabolism
Halflife in circulation: 1-2 minutes
- Metabolized quickly
* By protease in e.g. RBC
- Also removed by trapping mechanisms
Actions of angiotensin II
- Vasoconstriction
* One of the most potent vasoconstrictors known
- Stimulate release of aldosterone
- Increase thirst (dipsogenic effect)
* Via stimulation of subfornical organ (SFO)
* Organum vasculosum of the lamina terminalis (OVLT) may also be involved
- Stimulate release of ACTH
- Stimulate release of ADH
- Cause contraction of mesangial cells
--> decrease GFR
- Cause vasoconstriction of the arterioles
* Efferent arteriole vasoconstriction greater than afferent arteriole [WG21:p707]
- Potentiation of pressor effect
* By decreasing sensitivity of baroreflex
* Acts on area postrema
- Inhibit renin secretion
* Direct (negative) feedback to JG cells
- Direct effect on renal tubules to increase Na+ reabsorption
* [WG21:p460]
Angiotensin II receptors
2 classes: AT1 and AT2
AT1 receptors
- Coded on chromosome 3
- Coupled by G protein (Gq) to phospholipase C
--> Increases cytosolic free Ca2+ level
- Responsible for most known effects of angiotensin II
- Excess levels of AII
* Down regulates vascular AT1 receptors
* Up-regulates adrenocortical AT1 receptors (i.e. more aldosterone production) (special case)
AT2 receptors
- Coded on the X chromosome
- More in foetal life and neonatal life
- Physiological effect UNSETTLED
Regulation of renin secretion
Renin production is stimulated by
- Decrease in afferent arteriole BP
* Detected by intrarenal baroreceptor (JG cells)
- Decrease in NaCl content in filtrate entering DCT
* Detected by macula densa cels
- Stimulation of beta1-receptor on JG cells
* Via direct stimulation by renal sympathetic nerve (main)
* Can also due to circulating catecholamine
- Prostaglandins
* Especially prostacyclin
* Direct action on JG cells
NB:
- See "Intermediate-term control of BP" in Control of sodium and water excretion for more detail
- Renin secretion is also inversely releated to plasma K+ level
* But it is due to changes it produces in NaCl delivery to macula densa
Renin production is inhibited by
- Angiotensin II
* Negative feedback
- ADH (Vasopressin)
* Debate if effect is direct or indirect
* [WG21:p462]
- ANF (see Natriuretic hormones)
* [WG21:p383]
- K+ level
* Probably indirectly via its effect on NaCl delivery to macula densa
* [WG21:p462]
Pathological conditions causing elevated renin production
Volume-related
- Sodium depletion
- Diuretics
- Hypotension
- Haemorrhage
- Dehydration
Renal perfusion
- Cardiac failure
- Cirrhosis
- Renal artery stenosis
Others
Other notes
Tissue renin-angiotensin system
In addition to circulating angiotensin II, many tissues contain independent renin-angiotensin system that generate angiotensin II for local use.
Significance - UNSETTLED
Congestive heart failure
Characterised by high levels of renin, angiotensin II, aldosterone, catecholamines, and other mediators.