REB 24. Renin Angiotensin System Flashcards
What is the main driving pressure between the Intracellular Fluid (ICF) and Interstitial Fluid (IF)?
Osmotic Pressure
- e.g. ionic gradients
What is the main driving pressure between the Interstitial Fluid (IF) and Plasma?
Hydrostatic Pressure
- comes from the fluid inside the vessel pushing onwards
What compartment comprises of the largest total body water distribution percentage?
ICF comprises of 2/3 of TBW
ECF comprises of 1/3 TBW
What are the volumes of ECF and ICF present in the body?
65% ICF = 28L
35% ECF = 14L
What is the principle function of the renin-angiotensin system?
it controls fluid volume and blood pressure
- homeostasis
What happens to an individual in low blood pressure?
In low blood pressure, the oxygen perfusion is reduced
- causes lack of concentration, dizziness, nausea, fainting etc
then the RAAS responds!
Explain the RAAS system (the biochemical pathways) and processes involved.
[1] angiotensinogen synthesized in liver
[2] angiotensinogen converted to angiotensin I through the renin enzyme (endopeptidase)
*side note: renin is produced in the kidney
[3] angiotensin I is converted to angiotensin II through the ACE (angiotensin converting enzyme)
*side note: ACE is located in endothelial cells
[4a] angiotensin II converted to angiotensin III and angiotensin IV through the amino peptidase
[4b] angiotensin II activates to angiotensin II receptors which leads to a response
Response:
- tubular reabsorption
- aldosterone secretion
- vasoconstriction
- ADH release
— this increases the blood pressure!
Where is renin synthesized?
in the juxtaglomerular cells of the kidneys
Explain the process of the synthesis of renin. (e.g. what are the intermediates)
[1] Preprorenin (406 AAs) [2] Prorenin (383 AAs) [3] Renin (340 AAs) - stored in secretory granules - released in response to low BP - half life = 80 minutes - primary function is to cleave angiotensinogen to release angiotensin I
Where is renin stored?
in secretory granules
What is renin released in response to?
low BP
What is the half life of renin?
half life = 80 minutes
What is the rate-limiting step in the renin-angiotensin pathway?
renin
The activity of the renin-angiotensin system is measured clinically as?
PRA = Plasma Renin Activity
- used in diagnosis of patients with hypertension of hypotension
What is the juxtaglomerular apparatus made up of?
[1] Distal Convoluted Tubule
[2] Glomerular Afferent Arteriole
What are juxtaglomerular cells?
- they are specialized smooth muscle cells in afferent arterioles on entry to glomeruli
- they are site of renin synthesis
What is the Macula Densa?
- modified epithelial cells of the DCT close proximity to juxtaglomerular cells
- it senses NaCl uptake
- when they sense decreased NaCl uptake they stimulate prostaglandins and releases renin
What are the factors that stimulate renin secretion?
[1] Decreased BP in the Afferent Arteriole
- sensed by baroreceptors in the juxtaglomerular cells
[2] Decreased NaCl Reabsorption
- by Macula Densa Cells
- MD cells stimulate release of renin from JG cells via prostaglandins
[3] Increased Adrenergic Activity
- via sympathetic renal nerves + circulatory catecholamines
- induce renin release via beta-adrenoreceptors
- induce afferent arteriole constriction via alpha-adrenoreceptors
What are the factors that inhibit renin secretion?
[1] increasesd NaCl absorption across macula densa
[2] increased afferent arteriole pressure
[3] decreased sympathetic activity
[4] angiotensin II - negative feedback inhibition
What are some CONDITIONS that increase renin secretion?
[1] Low Blood Pressure
- sodium depletion
- diuretics
- haemorrhage
- dehydration
- heart failure
- cirrhosis of liver
[2] Fight or Flight
- sympathetic nervous system (increases circulating catecholamines)
- plasma adrenaline (circulating adrenaline)
What is a renin inhibitor that can be used to treat illness?
Aliskirin
- it is used to treat high blood pressure
Describe the synthesis and processes involved in creating Angiotensin II
[1] Angiotensinogen
- glycoprotein synthesized in LIVER
- renin cleaves Leu-Val bond of angiotensinogen to form Angiotensin I
[2] Angiotensin I
- physiologically inactive
[3] ACE converts Angiotensin I into Angiotensin II
- ACE primarily located in endothelial cells in LUNG
- a carboxypeptidase enzyme removes His + Leu from carboxy terminus of angiotensin I
Angiotensin II is the main what of RAAS?
main effector
What are ACE inhibitors important for?
important drugs for reducing blood pressure (e.g. captopril)
What are the 2 types of Angiotensin II receptors? Describe the function of each.
[1] AT1R (primarily mediates cardiovascular effects of ANGII)
- AT1A = principally in blood vessels
- AT1B = in adrenal cortex + anterior pituitary
[2] AT2R
- more plentiful in foetus and neonate (functions are unclear)
- activated by angiotensin III
What are the biological actions of Angiotensin II, specifically with the AT1R receptor?
[1] tubular Na+ reabsorption
[2] vasoconstriction
[3] aldosterone release
[4] ADH release
[5] inhibits renin release from JG cells
Explain how Angiotensin II stimulates sodium reabsorption
- stimulates sodium reabsorption in renal tubules, particularly in the PCT
- occurs via activation of AT1 receptors
- – stimulates the Na+/K+ ATPase pump on the basolateral membrane
- – stimulate NHE across the luminal membrane
- – stimulates Na+/HCO3- co-transport across the basolateral membrane
NET EFFECT: ANG II-induced increases in Na+ absorption driving water absorption
Explain how Angiotensin II stimulates vasoconstriction
- increases overall systemic BP
- in kidney, constriction of arterioles reduce filtration rate + urine production
- reduced pressure in peritubular capillaries increases reabsorption
In other words…
- decreased pressure leads to increase in resorption
Explain how Angiotensin II stimulates synthesis of aldosterone
- stimulates aldosterone in zona glomerulosa of adrenal cortex
- the zona glomerulosa of the adrenal gland…
- — lacks 17-alpha hydroxylase activity
- — has “aldosterone synthase” activity
What are some characteristics of aldosterone?
- mineralocorticoid
- half life of about 20 mins
- plasma levels vey low (0.17nmol/L) compared to cortisol (375nmol/L)
- weakly bound to plasma protein
- metabolised principally by liver
- principal function (enhanced reabsorption of Na+ from distal convoluted tubules of kidney)
What is hyperaldosteronism? What are the symptoms?
Hyperaldosteronism: too much aldosterone produced by adrenal glands
Symptoms:
- hypertension
- give/take hypokalaemia
What are the 2 types of hyperaldosteronism?
[1] Primary Hyperaldosteronism
[2] Secondary Hyperaldosteronism
What are the traits of Primary Hyperaldosteronism?
- defect in ADRENAL GLANDS
- increased levels caused by: adrenal adenoma (Conn’s syndrome) or idiopathic adrenal hyperplasia
- diagnosed by decreased serum + increased aldosterone (renin-aldosterone ratio drops)
What are the traits of Secondary Hyperaldosteronism?
- decreased renal perfusion caused by:
- — heart failure - decreased cardiac output
- — nephrotic syndrome
- — cirrhosis of liver
- — renal artery constriction (stenosis)
What is the diagnosis of primary hyperaldosteronism?
- decreased renin
- increased aldosterone
What is the treatment of hyperaldosteronism?
aldosterone antagonist (e.g. spironolactone)
What is hypoaldosteronism?
too little aldosterone produced by adrenal glands
What are the 2 types of hypoaldosteronism?
[1] Primary Hypoaldosteronism
[2] Secondary Hypoaldosteronism
What are the traits of Primary Hypoaldosteronism?
- occurs due to defective aldosterone release from the adrenals (e.g. Addison’s Disease)
- autoimmune destruction of adrenal gland
- — hypovolaemia with urinary Na+ loss and hyperkalemia
- — postural hypotension
- — dehydration
- — adrenal crises due to severe adrenal insufficiency (due to damage to adrenal gland)
What is the diagnosis of secondary hyperaldosteronism?
- increased renin
- increased aldosterone
What is the diagnosis of primary hypoaldosteronism?
- decreased aldosterone
- increased renin
What is the diagnosis of secondary hypoaldosteronism?
- decreased aldosterone
- decreased renin
What is the treatment of hypoaldosteronism?
mineralocorticoids
e.g. hydrocortisone, fludrocortisone + a high salt diet
Explain how angiotensin II stimulates the antidiuretic hormone secretion
- ADH is a peptide hormone produced in the pituitary gland
- acts at AVP receptors (GPCRs)
- half life of about 20 minutes
- primary functions:
- — vasoconstriction (mediated by AVP1R - Ca2+ release)
- — increase water absorption in in the kidney (AVP2R - mediated by AVP2R - cAMP production)
What is the function of antidiuretic hormone and how does it work?
ADH increases water absorption in collecting ducts
- due to increased luminal expression of Aquaporin 2
side note: ADH also promotes expression of urea transporters (UT-A) in the collecting duct
- – facilitates absorption of urea into the medullary interstitium
- – regulates fluid movement to and from collecting ducts
