RAAS: Salt and Renal Blood Flow Regulation - Slotki Flashcards
Map of hypotension effects
Where do these actions happen?
Renin-Angiotensin-Aldosterone system
Hypotension/hypovolemia causes renal hypoperfusion which causes decreased afferent arteriolar stretch and decreased NaCl delivery to macula densa (on distal tubule) which both cause increased renin release. Hypotension/volemia also cause increased sympathetic neural tone which increases renin release directly.
Gradient of response: highest in cortex, reduced gradually in medulla. Activation of renin regulated in the cortex. (Medulla is more hypoxic generally).
What happens when Renin is increased? Where?
Triggered from decreased ECF volume
In proximal tubule cells:
Converts angiotensinogen to angiotensin I which is converted to angiotensin II by ACE I (which also converts bradykinin to inactive fragments). Angiotensin II can also be formed from Non-ACE pathway from angiotensinogen. Fragments of angiotensin II are formed from peptidases to form ang III and IV. ACE 2 forms angiotensin 1-9 which forms angiotensin 1-7 from ACE1.
Local systems in the proximal tubule, smooth muscle of vascular endothelium, adrenal and brain.
Poorly correlated with tissue activity
Low renin HTN may be associated with high tissue levels (but still respond to ACEi)
In essential HTN, PRA not predictive of response to ACEI or AIIR antagonists
What are the angiotensin II receptors and their effects?
AT1 receptor acts on second messengers:
G-protein coupled
cAMP
Ip3/DG
Effects: Inccreased aldosterone secretion and direct renal Na+ reabsorption–>ECF volume expansion–> decreased renin release which is also caused by increased systemic BP.
May facilitate neovascularization
Induction and migration of neointima formation (SMC proliferation)
May facilitate neovascularization
AT2:
Signal transducers:
Non-G-protein coupled
Tyrosine phosphatase
Other unknown effects
May modulate neovascularization
Attenuates neointima formation (SMC proliferation)
May control tumor growth
No useful pharmacological use yet
Hemodynamic Effects of angiotensin II
Renal sodium and water retention
Through decreased cAMP–>decreased protein kinase A–>enhanced Na/H antiporter to increase intracellular [Na+]
Increased PKc through Gp coupled receptor.
Systemic vasoconstriction
Constriction of vascular smooth muscle cells through IP3 (–>increased Ca) and DAG (increased arachidonic acid and PKc)–> vascular smooth muscle contraction
Regulation of GFR
AngII vasoconstricting efferent and afferent arterioles through TXA2 (end result, more in efferent)
PGE2 vasodilates them (more afferent)
Leading to decreased renal blood flow
Mesangial contraction through increased PGc means decreased area for filtration and net result is no change in GFR
Effects of RAAS on the glomerulus in renal artery stenosis
Decreased GFR, increased serum creatinine
Effective constriction of the afferent arteriole from decreased renal perfusion pressure
Maximum dilation of the efferent arteriole from PGE2
If given ACEi, blocked angiotensin II means inhibited constriction of the efferent arterioles drops GFR further (more increased Pcr)
Control of renin secretion- what are the factors?
Decreased Na intake–>decreased ECF volume –> acute increase in renin release (or chronic prorenin release which leads to renin release) –> increased AngII ——> increased aldosterone –>decreased Na excretion or increased reabsorption and volume reset
Decreased ECF volume longterm decreases renal perfusion pressure –> increased renin secretion
Cl- sensor (macula densa) decreases Cl- delivery to distal tubule through PGE2 causes increased renin secretion
Baroreceptors cause increased sympathetic NS activity –> increased catecholamines –> renin secretion (beta blocker prevent effect of catecholamines)
Hormonal actions of aldosterone
Epithelial cells
Non-epithelial cells
CV effects
Apparent genomic effects
Endothelial function
VSMC effects-inflammation, lipid oxidation, microvascular injury, fibrogenesis
Apparent non-genomic effects
CNS effects
Central
Peripheral; baroreflex sensitivity; sympathetic flow
Increased K+ urinary excretion
Decreased Na+, Cl- goes with
Increased NH4+ excretion
Receptor inside the cell promotes entry of Na through luminal membrane channel and then reabsorption through Na/K ATPase. Net Na absorption and K excretion.
Control of aldosterone secretion
(High) Plasma K+ biggest regulator (through aldosterone)
RAAS (through AngII)
ACTH (like cortisol will increase aldo and through deoxycorticosterone)
Decreased Plasma Na+effective oncotic pressure
Extracellular pH increase (get rid of more H+)
ANP–> decreased Aldo
AngII and K act at 2 points of steroid production:
- Enzyme that converts cholesterol to pregnenolone
- Aldosterone synthetase (corticosterone to aldosterone)
Because AngII and plasma K levels all affect aldo release, ACEi’s decreased AngII means aldo is not getting rid of K and can cause life threatening hyperkalemia especially in patients with beta blockers, decreased aldo and ACEi and hypovolemia
Why is there little interference between K and Na systems?
K+ secretion highly dependent on Na & water delivery to CCT
K+ balance influences Thick ALH Na+ reabsorption
Na depletion: Ang II leads to increased prox tubule reabs of Na and thus decreased delivery to distal tubule. Decreased Na urinary excretion. No Na available for K excretion through ATPase.
K+ load: Lots of K to ThAL then Na/K/Cl cotransporter is inhibited. If overall K load (inside the cell) then reduce driving force for cotransporter. Increased distal Na tubular content and so aldo can act to excrete K in exchange for Na reabsorption in distal tubule and decreased Na more proximally so no net effect on Na transport.
Causes of mineralocorticoid excess
Primary hyperaldosteronism
-Adenoma (suspect in resistant HTN and hypokalemia or normokalemia if of ACEi, aldosterone/ratio should correlate)
-Hyperplasia (eg. GRA-ACTH leads to high aldo and cortisol)
-Carcinoma
Cushing’s disease
Congenital adrenal hyperplasia
-17a-hydroxylase deficiency
-11b-hydroxylase deficiency
Chronic exogenous mineralocorticoid
Hypereninism
-Renal artery stenosis
-Renin-secreting tumour
Hypersecretion of DOC etc induced by licorice
Na+ channel activation
Bartter’s syndrome
Liddle’s Syndrome
Autosomal dominant
Severe HTN
hypoK+
Met alkalosis
Low aldosterone
Low renin
Constitutive activation of alpha and beta subunits
Hypokalemia should respond to spironolactone if K levels are high but in Liddle’s syndrome don’t have high aldosterone so don’t. Triamterine prevented Na resorption from apical membrane so transporter in apical membrane transports Na overworked
Secondary Hypoaldosteronism mechanism
In distal tubule: luminal side: ROMK and Na/Cl cotransporter. Basolateral side: Na/K ATPase and AT1R. In lumen: WNK1-4 and SPAK.
In hypovolemia: high angII and aldo. AT1R in prox and distal tubules stimulate WNK4 stimulation. Aldosterone signal mediated by SGK1 which also phosphorylates WNK4. P-WNK4 cascade phosphorylates SPAK that stimulates Na/Cl cotransport which leads to an increase in Na reabsorption in the distal tubule.
Hyperkalemia: Low AngII. WNK4 dephosphorylated. Na/Cl cotransporter inactive. High aldosterone stimulates kidney specific (KSWNK1) which inhibits L-WNK1. Blocks phosphorylation of SPAK (normally phosphorylated from LWNK1). If SPAK not phosphorylated Na/Cl not phosphorylated (again). Dephosphorylated WNK1 allows ROMK to insert into membrane. Allows K secretion/excretion. SGK1 aldosterone activated and helps ROMK insertion.
Bartter’s Syndrome
Clinical findings
3 variants
Secondary hypoaldosteronism
Hypokalemia
Hypochloremia
Metabolic acidosis
Increased UK
Increased UPGE2
Normal or low BP
Increased renin and aldosterone
A. Hypercalcuric variant
Hydramnios
Prematurity
Dehydration at birth (often fatal)
Increased calcium in urine
B. Classical
Failure to thrive
C. Gitelman’s syndrome
Adults
Hypocalcuria
Hypomagnesemia
Hypokalemia primary presentation
Mutation in medullary thick ascending limb (mTAL) cell
Classical mutation is NKCC2 (bocking lumenal K, Cl and Na entry into cell).
Secondary paralysis: in ROMK lumenal channel
Another mutation: Barttin transporter of ClC-Kb channel (reabsorbing Cl- on basolateral side)
All have the same effect
Gitelman Syndrome
Mutation in distal tubular cell
Divalent metal transporters
Knockout of Na/Cl cotransporter.
Theory: Mg and Ca transport is affected
Divalent metal antiporters somehow affected
Bottom line: Ca reabsorbed but Mg not, hypocalciuria and hypomagnesemia
Types of etiology of hypoaldosteronism, causes and mechanisms
Decreased activity of RAS
Most common
Hyporeninemic hypoaldesteronism with mild to moderate CRF –> hyperkalemia
NSAIDs (worsens hyperkalemia and also inhibits PGs which allows AngII unopposed effect)
ACEI
Cyclosporine (inhibits renin and aldosterone)
AIDS (HIV nephropathy leads to tubular interstitial damage)
Hypervolemia in chronic dialysis patients-suppresses aldosteronism. No urine–>hyperkalemia
Primary decrease in adrenal synthesis
Low cortisol levels
-Primary adrenal insufficiency (Addison’s)
-Congenital adrenal hyperplasia:
primary 21-OH-ase deficiency
Normal cortisol levels
-Heparin
Isolated hypoaldosteronism (rare)
Post-removal of adrenal adenoma
Aldosterone resistance (normal or high levels) K+ sparing diuretics (act as aldosterone analogue) ENAC inhibitors (like triampterene for LIddle's) Cyclosporine Pseudohypoaldosteronism (rare)
