the Proximal convoluted tubule and transport mechanisms Flashcards
body fluid distribution
intracellular fluid - 40%, 25L
extracellular fluid:
interstitial fluid - 15% 10-13L
plasma - 5% 3L
normal plasma values for a human
pH = 7.35
osmolality = 300 mOsm/ Kg H20
Na+ = 145 mmol/l
K+ = 4.5 mmo/l
cl - = 100 mmol/l
glucose = 3.5 - 5.5mmol/l
urea = 5 mmol/l
normal urine values for a human
pH = 5.0-7.0
osmolality =100-200 mOsm/ Kg H20
Na+ = 30-130 mmol/l
K+ = 20-100 mmo/l
cl - = 30-130 mmol/l
glucose = 0 mmol/l
urea = 200-400 mmol/l
what is the main product of kidney function
urine production
3 processes of kidney function
- filtration at glomerulus plasma -> filtrate
- reabsorption of water and solutes
- secretion of solutes into tubular fluids
proximal convoluted tubule features
- long length so increased surface area
- microvilli
- mitochondria for active transport
function of PCT
When things are filtered at the glomerulus they enter the Bowman’s capsule and straight
Away We get Bulk reabsorption
- anything the body wants to keep hold of gets reabsorbed straight away.
- reabsorbs a greater variety of substances than other parts of the nephron
- water 65% (osmosis), sodium (65-67% (mainly by active transport and 25% other mechanisms, glucose 100% (secondary active transport), amino acids 100% (secondary active transport), urea 44%
PCT tubular secretion
- this is where things go from the plasma back into the filtrate back into the tubules
- and the main things there that gets secreted are things like hydrogen ions to help balance the pH
○ And also some large organic anions.
So we’ve got these specialized Transporters in the proximal convoluted tubule called oats
how are substances reabsorbed/ secreted
- diffusion via tight junctions between tubular epithelial cells
- mediated transport which requires the involvement of plasma membrane transport proteins e.g. exchangers, SGLT, OATs
the sections of the PCT
S1 down to S3
- S1 is near the Bowman’s capsule So when fluid first enter the proximal convoluted tubule We’ve got a smaller Lumen and we’ve got many more microvilli there.
○ So it’s a really extensive environment to get that reabsorption
- as we move further down towards the loop of henle We find the lumen gets bigger and we’ve got less microvilli there.
different ways solutes are transported
passive-down conc/ electrical gradient
facilitated - carrier proteins (carrier-mediated)
active - energy-requiring transport
endocytosis
passive transport/ diffusion
movement down a concentration gradient.
things can move passively from a region of high concentration to lower concentration down the concentration gradient, or we can also get things moving down an electrochemical gradient
it’s easy if we’ve got an open pore or we’ve got a channel we can therefore just move by passive diffusion.
two main routes of reabsorption in the PCT
- transcellular passport Pathways and para-cellular Pathways
○ para cellular means that things can be reabsorbed or secreted between the cells. - the transcellular route is where we move through the cell.
- So to do this, we’ve got to utilize Transporters potentially on both membranes.
water transport
passive
solvent drag
when water is being reabsorbed. There are dissolved ions in the water And therefore they can also get reabsorbed as the water moves by osmosis Sometimes you can have Dissolved electrolytes in there that also get taken along
how does water move
water moves by osmosis
○ The way water moves is through aquaporins.
○ the first aquaporin to be discovered in the proximal convoluted tubules was aquaporin one
facilitated diffusion
- movement of large molecules that can’t cross the plasma membrane
- solutes require interaction will cell membrane proteins e.g. Na+ or K+ to allow movement through aqueous fluid-filled channels created by proteins spanning the membrane or transporters
properties of channels
-A channel is where we have a transmembrane protein that allows an iron or a solute to pass across a membrane.
-can be open or closed
- selectivity: non selective or ion selective
- electrogenic (for ions) or electroneutral (i.e. H20)
- permeability depends on the number of channels in an area of membrane and probability that channel is open or closed
transporters
A channel is where we have a transmembrane protein that allows an iron or a solute to pass across a membrane.
uni-port
one substance moves down its concentration gradient
- the same number of molecules bind to the outside of the transporter as bind to the inside
- allows movement by diffusion of large polar molecules i.e. glucose (GLUT-2 on basolateral membrane)
cotransporter or symporter
more than 1 solute in the same direction
e.g. NKCC
antiporter or exchanger
more than 1 solute in opposite directions e.g. Na+/ H+
primary active transport
move substances against conc/electrochemical gradient
- requires a membrane protein
- required the hydrolysis of ATP
secondary active transport
- usually involves Na+ moving from a high concentration to a low concentration
- whereas the other solute is moving from a low concentration to a high concentration
types of mediated transport
uniport - glucose
ATP utilising transporters - Na+/K+ ATPase
symport - Na+/glucose (SGLT), Na+/AA
antiport - 1 H+ secreted, 1 Na+ reabsorbed
SGLT and GLUT
SGLT2 - GLUT 2
- 1 Na + transported
SGLT1- GLUT 1
- 2 Na+ transported
in the early proximal convoluted tubule, we’ve got more of the sglt2 which corresponds
to glut2 to on the basolateral membrane and sGLT one is further down in the later proximal convoluted tubule.
what happens if glucose remains in the filtrate
what can happen is it then draws in water because glucose is osmotically active
what happens when SGLT transporters are compromised
diabetes mellitus
- the body can’t control plasma glucose levels. so glucose levels in the plasma rise.
- glucose can be filtrated at the glomerulus. So it passes into the PCT. It enters the PCT and then all the sglt2 Transporters quickly reabsorb the glucose in a healthy individual
○ in somebody with diabetes, the concentration of glucose in The plasma is really high so you don’t get that same concentration gradient, but also because there’s so much glucose being filtered at the glomerulus, It’s saturating all of those sglt transporters.
○ So what happens is because the saturated they become overwhelmed and therefore we have glucose remains in the filtrate.
glucose in urine during pregnancy
There is something in pregnancy where you can get glucose in urine. This isn’t to do with changes in the Transporters.
- This is where usually the renal threshold Falls slightly because during pregnancy you can get changes in GFR because of the change in the circulatory volume in the mum and obviously the fetus so that can alter sensitivity there.
- You also have changes in hormone levels which can also alter insulin secretion
SGLT 2 inhibitors - treatment for type 2 Diabetes mellitus
- gliflozins usually used in combination therapy
- reduce glucose reabsorption in the PCT
- reduce plasma glucose levels
- increase UTI
- issues with patients with poor renal function
endocytosis
usually, small proteins are taken from filtrate back into the cell
- invagination of protein requires ATP
organic anion transporters - OAT1
tissue: kidney, basolateral membrane, PCT
substrates: broad selectivity, e.g. prostaglandins, cyclic nucleotides
OAT 2
tissue: liver, weak in kidneys
substrates: aspirin
OAT3
tissue: brain, kidneys basolateral membrane/ liver/ eye
substrates: various drugs e.g. cimetidine
OAT4
tissue: human kidney
substrates: Na+ independent prostaglandins
OAT5
tissue: rat kidney, apical membrane of PCT
substrates: steroid sulphates
how do OATs function
we find them on the basolateral membrane in the proximal convoluted tubule
- they’re involved in secretion, So normally the amino acid glutarate is metabolized
- as it’s metabolized It produces Alpha ketoglutarate
○ This will be taken out of the cell back into the plasma And as that happens the organic anions can all then utilize this transporter and take into the cell
sodium transport
- 60-70% reabsorbed in PCT
couple to: glucose, AA, lactate, H+, Cl-, K+, K+2Cl- - later in nephron Na+ channel
sodium is the driving force
- sodium can utilize primary active transport with sodium potassium atpase - really important transporter found on the basolateral membrane.
Sodium can also be coupled to many different things in the proximal convoluted tubule.
HCO3- transport
- bicarbonates really important reabsorption for acid-base balance
- We have the presence of an enzyme ( Carbonic anhydrase) - Carbonic anhydrase combines carbon dioxide and water to form carbonic acid
- carbonic acid is unstable So it dissociates into protons and bicarbonate ions.
○ This is a reversible reaction that’s going on in many cells
reabsorption of bicarbonate in PCT
The proximal convoluted tubule cells have water and carbon dioxide from the filtrate
- These can diffuse into the cell.
- Inside the cell, we’ve got Carbonic anhydrase 2 and this can allow the conversion of carbon dioxide and water to carbonic acid to produce protons and bicarbonate
- bicarbonate can be reabsorbed on the basolateral membrane with the sodium bicarbonate transporter
And we’ve also got an exchanger which is where sodium can be exchanged for chloride
carbonic anhydrase 4 in PCT
We also have Carbonic anhydrase 4 which is a membrane-bound Carbonic anhydrase, which is found bound to The membranes of the proximal convoluted tubules in the Lumen - So where we have the filtrate
- and what that means is if we get carbon dioxide and water here, we can also produce bicarbonate protons here to allow the constant Supply to keep the bicarbonate reabsorption occurring if needed.
So Carbonic anhydrase is found both inside the cytoplasm and there’s a form that’s membrane bound so that same reaction can occur in both areas
potassium transport
- passive 60-70% movement - solvent drag in early PCT
- primary active transport of K+ with Na+ in PCT - reabsorbed/ secreted in PCT and further down nephron
- secondary active transport of potassium with sodium and chloride in loop of Henle
what is urea
- a breakdown product of amino acid metabolism
where is urea filtered, secreted, reabsorbed
- filtered at glomerulus
- urea is freely secreted and absorbed tubular membranes
- passive reabsorbed (and by solvent drag in PCT) and by diffusion in medullary collecting duct
how is urea transport dependent on water transport
- as water diffuses across PCT membrane into interstitial fluid, this increases concentration of urea in tubular fluid
- so urea moves down concentration gradient back into plasma in peritubular capillaries
- hence urea transport is dependent on water transport
- secreted in LOH via urea transporter (UT2)
Familiar renal glucosuria
- genetic disorder
- mutation in Na+/glucose active transport mechanism in the renal PCT
- inadequate reabsorption of glucose in PCT glucose lost in urine
- very different to diabetes mellitus where transporter saturated
