sodium homeostasis disorders Flashcards
why is sodium homeostasis important
key regulator of fluid volume
determines excitability of cells (muscle, cardiac, neuronal)
controls arterial BP
how does the osmotic pressure of filtrate change along nephron?
isoosmotic at Bowmans capsule and PCT as equal sodium and water reabsorb
down into medulla, filtrate osmolarity increases (hypertonic) as impermeable to ions so only only water reabsorbed (600 to 1400 mOsm)
towards DCT and CD to 90mOsm (hypotonic filtrate) as impermeable to water so only ions are actively pumped out
where is most of sodium reabsorbed along nephron?
pCT 60-70
loH/ TAL 25%
CD and DCT 5% each
why does the osmolarity around loop of henle change so much? what is the advantage?
different permeabilities of the ascend and descend limb which create different concentration gradients
allows control of water (and ion) reabsorption
how does ADH influence water reabsorp?
introduced Aquaporins to increase water reabsorption
creates CONCENTRATED urine
acts to conserve water
why is the basolateral Na/K atpase important in the PCT for sodium transport?
active transport removes sodium from intracellular space
this provides an electrochemical gradient for the apical transporters to passively transport sodium into cell
what is special about sodium reabsoprtion at the PCT?
sodium reabsorp is coupled to chlorine transport too!
what are the 2 types of CD cells? what is their functions
primary CD cells transport sodium / influence fluid volum
intercalated CD cells transport H+/ influence pH
how can NKCC2 be regulated?
channel present in the TAL
regulated by aldosterone
which activates SPAK1 kinase -> phosphroylate and activates NKCC2
what is the difference between type A + B intercalated duct cells?
type A transport H+
type B transport BICarbonate ions
very important to regulate pH balancw
describe strucutre of ENaC channel. Where is it found?
found at principle CD cells but can be found in other organs too
in kidney it is a heterotrimeric structure with alpha,beta and gamma subunits
what are some electrophysiological features of ENaC?
voltage and ligand independent channel
it is constiuitively open!
how is ENaC regulated?
by Nedd4-2 protein which ubiquinates and marks for internalisation + degradation
by SGK1 that phosphorylates and activates and increases OPEN PROBABILITY of channel! And increases ROMK channel activity and can inhibit Nedd4-2
how does ADH/AVP regulate activity of ENaC?
binds to receptor activating signalling cascade involving PKA
phosphorylates AQ2 and ENaC increasing their activity and ROMK secretion
reabsopb increases, concentrated urine produced
how does aldosterone influence ENaC activity?
expression of SGK1 increases so open probability of channel increases
conformation of inhibitory Nedd4-2 changes
promotes sodium reabsorp
what is CAP1?
Cap1 is a extracellular protein which can proteolytically cleave gamma subunit of ENaC
increase its open probability
where and why is aldosterone produced?
mineralcorticoid produced in zona glomerulosa of adrenal cortex in response to increased Angll (RAAS) or increased plasma K+
acts to increase sodium reabsorp/ increase BP and fluid volume
where and why is ANP produced?
small peptide secretred from atria muscle in response to stretch/increased fluid volume
aims to reduce BP/ reduce sodium reabsorb by inhibiting the ENaC, inhibit RAAS
what is the end aim of RAAS?
increases ADH and aldosterone secretion amongst other actions (vasocontrict, SNS activity)
to increase the BP
where is cortisol produced? what is the rate limiting enzyme?
cortisol, a glucocorticoid is produced in zona fasciulata
11-beta hydroxylase is rate limiting enzyme
what is the mutation in Liddle’s syndrome
GoF of ENaC as the PY motif on beta and gamma subunit is mutated
so Nedd4-2 unable to recognise, internalise and degrade ENaC
so ENac persists on apical CD membrane and continues to reabsorb sodium
is the genetic cause of all Liddle’s syndrome the same?
No!
some novel mutations have been uncovered but same end result which is GoF of ENaC
how would one treat Liddle’s syndrome
use ENaC pore blockers like Amirolide
this would reduce BP and blood volume
what is the cause of glucocorticoid remediable Aldosteronism?
chimeric gene affecting biosynthesis of cortisol and results in excess aldosterone production
due to ACTH signalling
how would one treat glucocorticoid remediable Aldosteronism
use corticosteroids to correct the HPA axis and stop signalling of ACTH
e.g dexamethosome, a synthetic glucocorticoid
what are symptoms of increases aldosterone
over activity of ENaC channel so hypertension,
overactivity of ROMK channel so hypokalcemia
hyporeninemia from the RAAS system
what happens in apparent mineralcorticoid excess?
there is a deficit in 11-beta dehydrogenase activity so cortisol isn’t converted to cortisone
this overstimulates the mineralcorticoid receptro
what are the consequences of overactive mineral corticoid receptor:
activates same signalling pathways as aldosterones
so increased sodium and water reabsorb, increased pottassium wasting
how does liquorice consumption affect sodium homeostasis?
liquorice contains compounds which stimulate the Mcorticoid Receptor
so can lead to hypotensive disorder
how to treat Apparrent mineral corticoid excess?
block ENaC with pore blocker like Amirolide or Benzamil
how do diuretics work? / what is their aim
aim to create concentrated urine
so increase water reabsorption
how do diuretics work
the severity/ potentcy of each diuretic depends on which area of the nephron they target
target different proteins involved in sodium (and hence water) transport and block their activity
which of the diuretics are most potent?
thiazide
potassium sparing
loop
acetazoliimde
loop diureitc most potent
targets the NKCC tri-cotransporter and blocks it (mimics Bartters syndrome)
what causes Bartters syndrome?
mutation of NKCC2 in the TAL so has reduced function
this has downstream affects on the NCX1 transporter and works against conc. grad. So calcium reabsorb decreases
what is the key differences in Bartters and Gitelmans
B - mutation at TAL but affects transport at DCT decreasing NCX1 function. So results in hypocalcemia
G - mutation at the DCT, NCX1 function increases,
hypercalcemia
how to treat Bartters syndrome?
can give potassium sparing diuretics to increase water + sodium excretion
what causes Gitelmans syndrome
NCC in the DCT mutated and has LoF
how to treat Gitelmans
use NaCL and KCL supplements and Mg
NSAIDs to block COX activity
potassium sparing diruretics can be used to prevent any futhur secretion of K+
what is the relationship between sodium and potassium?
because of the Na/K atpase, they move in opposite directions
so if hypotension, then hypokalemia also ??????
what does COX enzyme do?
wasting of NaCL activates the COX enzyme
so there is elevated prostaglandin synthesis
prostaglandins are pro -inflame so patiens can feel vomit, nausea
what casues pseudohypoaldosteronism
LoF of ENaC or the McorticodiR in collecting duct
why is it called pseudohypoaldoseronism?
actually patients have high aldosterone levels to try and correct the the hypotension
but as ENaC or receptor is faulty, the collecting duct cells are unresponsive to the aldosterone signalling
so symptoms of hypoaldosterone remain, despite actual plama aldo is high
how would one treat pseudohypoaldosteronism?
use NaCl supplements,
ion exhcnage resins too
