REB 24. Renin Angiotensin System Flashcards by Jennita Ariaratnam

What is the main driving pressure between the Intracellular Fluid (ICF) and Interstitial Fluid (IF)?

Osmotic Pressure

- e.g. ionic gradients

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What is the main driving pressure between the Interstitial Fluid (IF) and Plasma?

Hydrostatic Pressure

- comes from the fluid inside the vessel pushing onwards

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What compartment comprises of the largest total body water distribution percentage?

ICF comprises of 2/3 of TBW

ECF comprises of 1/3 TBW

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What are the volumes of ECF and ICF present in the body?

65% ICF = 28L

35% ECF = 14L

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What is the principle function of the renin-angiotensin system?

it controls fluid volume and blood pressure

- homeostasis

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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!

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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!

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Where is renin synthesized?

in the juxtaglomerular cells of the kidneys

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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

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Where is renin stored?

in secretory granules

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What is renin released in response to?

low BP

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What is the half life of renin?

half life = 80 minutes

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What is the rate-limiting step in the renin-angiotensin pathway?

renin

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The activity of the renin-angiotensin system is measured clinically as?

PRA = Plasma Renin Activity

- used in diagnosis of patients with hypertension of hypotension

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What is the juxtaglomerular apparatus made up of?

[1] Distal Convoluted Tubule

[2] Glomerular Afferent Arteriole

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What are juxtaglomerular cells?

they are specialized smooth muscle cells in afferent arterioles on entry to glomeruli
they are site of renin synthesis

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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

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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

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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