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

1. Vasoconstriction
   * One of the most potent vasoconstrictors known
2. Stimulate release of aldosterone
3. Increase thirst (dipsogenic effect)
   * Via stimulation of subfornical organ (SFO)
   * Organum vasculosum of the lamina terminalis (OVLT) may also be involved
4. Stimulate release of ACTH
5. Stimulate release of ADH
6. Cause contraction of mesangial cells
   --> decrease GFR
7. Cause vasoconstriction of the arterioles
   * Efferent arteriole vasoconstriction greater than afferent arteriole [WG21:p707]
8. Potentiation of pressor effect
   * By decreasing sensitivity of baroreflex
   * Acts on area postrema
9. Inhibit renin secretion
   * Direct (negative) feedback to JG cells
10. 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

1. Decrease in afferent arteriole BP
   * Detected by intrarenal baroreceptor (JG cells)
2. Decrease in NaCl content in filtrate entering DCT
   * Detected by macula densa cels
3. Stimulation of beta1-receptor on JG cells
   * Via direct stimulation by renal sympathetic nerve (main)
   * Can also due to circulating catecholamine
4. 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

• Upright posture

 

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.