Lecture 14 - bicarbonate Flashcards
Plasma HCO3 is approx
25mM
how much fluid is filtered daily by kidney?
180L
Amount of HCO3 filtered daily
approx. 4.5 moles
Proximal tubule absorbs …% of HCO3
80%
proximal tubule apical membrane
Na+/H+ co-transporter and H+ATPase with CAIV tethered
Proximal tubule HCO3 reabsorption process
H+ secreted into lumen to combine with HCO3 to form H2CO3 in presence of H2CO3 by CAIV then splits into H2O and CO2
CO2 enters via apical membrane and combines with H2O by CAII to then break up to H+ and HCO3
HCO3 leaves the basolateral membrane via HCO3/Na cotransporter
HCO3/Na co-transporter
can work in 1Na:3HCO3 or 1Na:2HCO3
1:2 bicarbonate sodium cotransporter drives
drives UPTAKE into cell
1:2 bicarbonate-sodium cotransporter drives
reabsorption of HCO3
HCO3 reabsorption stimulation
angiotensin II, endothelia I, noradrenaline and adenosine, which is linked to calcium increases and PKC
HCO3 reabsorption down regulated stimulated by
ANP, parathormone and dopamine, linked to cAMP/PKA pathway
CO2 receptor control fo HCO3 absorption
level of blood CO2 acts to inhibit or stimulate
PT sense blood CO2 levels and alters HCO3 transport accordingly
proximal tubule removal of HCO3
increased HCO3 reabsorption, though to maybe reduce back flux through tight junctions and increase exit gradients
Proximal tubule removal of CO2
reduced HCO3 absorption, hypothesised CO2 receptor sensed blood CO2 levels
Proximal tubule calcium channels
addition of HCO3/CO2 to lumen has no effect, but into the bath it increases calcium
Showed CO2 was responsible for calcium increase
Inhibiting receptor protein kinases
abolished levels between CO2 levels and HCO3 transport
protein tyrosine phosphatase Y location
proximal tubule basolateral membranes
protein tyrosine phosphatase KO mice
fixed pH and HCO3 levels on basolateral but change CO2 which inhibited HCO3 transport
KO mouse does not respond to CO2
clamped CO2 and changed HCO3 to find KO insensitive to HCO3 levels
protein tyrosine phosphatase Y hypothesis
when CO2 binds to phosphatase it causes inhibition of phosphatase activity therefore receptor protein kinases are upregulated/dominant
HCO3 transport experiment
split-drop micro puncture techniques, introduced fluid drop into PT in between oil drops and measured droplet volume with time. Varied droplet composition and fluid in capillary perfusate, measure rate of change of droplet volume which is proportional to water permeability/flux across PT
Removal of HCO3 = rate of change goes down
Added DIDS = reduced water reabsorption
HCO3 absence = water reabsorption by PT is greatly reduced
NHE3 KO mice
decreased BP, plasma pH and HCO3
NHE3 conclusion
NHE3 drives 60% HCO3 reabsorption and 70% of H2O reabsorption in mouse PT
so H+ pump is not being unregulated for compensation
pancreatic duct HCO3 secretion
CO2 enters cell, reacts with H2O to form H2CO3, splits to HCO3 and H+. HCO3 leaves cell via apical exchanger
H+ recycled across basolateral channel
pancreatic duct apical membrane
Cl/HCO3 exchanger and CFTR
Pancreatic duct basolateral membrane
Na/HCO3 cotransporter
H+/Na exchanger
pancreatic duct luminal HCO3 conc increase
inhibits the anion exchanger and electrochemical gradients established favour continued HCO3 secretion
SLC and CFTR resting conditions
both inactive, CFTR regulator domain interacts with nucleotide binding domains which inhibit channel action
SLC and CFTR PKA stimulation
phosphorylation of CFTR regulatory domain and inhibition of CFTR is released and it acts as a HCO3 channel, also reacts with SLC regulatory domain to promote Cl/HCO3 exchange
Pancreatic sufficiency is linked to…
ability of CFTR to transport HCO3
