Tubular reabsorption Flashcards
What is the proximal tubule?
The early part is the proximal convoluted tubule.
The rest is the proximal straight tubule.
It is lined with epithelial cells which have microvilli projecting into the lumen, and form a brush border.
How does transport occur in the proximal convoluted tubule?
The PCT uses both primary and secondary active transport.
Some movement is transcellular - through cells.
Some movement is paracellular - between the cells.
The electrochemical gradient of Na+ is used to drive the reabsorption of substances.
What is the osmolality of the proximal tubule?
The PCT is quite water permeable, implies filtrate is isotonic (same) with the interstitial space - the plasma.
The solute moves and then water moves until it equilibrates.
What is the layout of movement in the proximal tubule?
Apical surface - faces filtrate
Basolateral surface - faces cortical interstitial space, connected to venous system.
What are the different forms of movement in the proximal tubule?
Reabsorption - movement from filtrate to cortical interstitial space.
Secretion - moving from cortical interstitial space into filtrate, to form urine.
How does water move paracellularly in the proximal tubule?
Water moves paracellularly - in between cells, due to the net outward hydrostatic and osmotic forces.
It can pass through the tight junctions because they are leaky.
How does water move transcellularly in the proximal tubule?
Through protein channels - aquaporins (AQP1), which are inserted into the basolateral and apical membranes.
This is driven by hydrostatic pressure and osmotic pressure.
How is water movement driven in the proximal tubule?
As filtrate is formed, it is pushed through by the pressure in circulation, which creates hydrostatic pressure in filtrate, which pushes the filtrate out.
Osmotic pressure, as salts (Na+, Cl-) are absorbed, creates small pressure in cortical interstitial space.
What are the fates of molecules along the proximal tubule?
Inulin - not absorbed, higher concentration at end of tubule.
Urea - weakly absorbed, higher concentration at end.
Chloride - weakly absorbed, higher concentration at end.
Na+, K+ - absorbed, same concentration at end.
HCO3- - absorbed, lower concentration at end.
Amino acids - strongly absorbed, much lower concentration.
Glucose - strongly absorbed, much lower concentration.
What is the relationship between absorption and concentration?
Concentration is the ratio of amount of substance / volume of solvent.
Higher concentration at end, increase amount of substance, or decreased volume of water.
A substance not absorbed will increase in concentration.
Substance absorbed at same rate as water (Na+) concentration is same.
Strongly reabsorbed - lower concentrations.
How does glucose move in the proximal tubule?
Main transport is via the SGLT2 co-transporter.
This uses the electrochemical gradient of Na+ to drive glucose into the cell across the apical surface.
When glucose has high concentration in cell, use facilitated diffusion GLUT2 channel to move glucose into cortical interstitial space down concentration gradient.
How does glucose move in the proximal tubule when the concentration is low?
Along proximal tubule, glucose concentration falls, so harder for glucose to be absorbed as it is against the concentration gradient.
So SGLT1 co-transporter can be used to transport 2 Na+ and drive glucose into cell as there is more energy.
Glucose then crosses basolateral membrane through GLUT1 by facilitated diffusion down the concentration gradient.
What is Tmax?
Cotransporters (SGLT1/2) have a finite rate at which they can work.
Only so much time in PCT for reabsorption to take place.
Tmax is the maximum rate at which glucose can be reabsorbed.
What is the glucose concentrations and rate when normal?
Concentration of glucose filtered is the same as concentration in plasma, as glucose is small so is not stopped by glomerular layers.
When normal concentration, glucose filtered is proportional to the concentration in the urine.
The amount of glucose reabsorbed is equal to the filtrate, and the amount of glucose in the urine is negligible.
What is the glucose rate when glucose concentration is not normal?
When there is high sugar, or the pancreas is not working, the transporters are at maximum capacity, so the amount of glucose reabsorbed stops.
The extra glucose goes into the urine and is excreted.
What does the glucose uptake and excretion graph look like?
See image.
The amount of glucose excreted is the difference between the filtered and reabsorbed rates.
When the transporters are at full capacity, the difference becomes real, and the glucose is excreted.
What is the mechanism against high glucose concentration?
The kidney uses the mechanism of Tmax to counteract high glucose concentrations, and excrete glucose.
Tmax is also used by other body systems for other substances high concentrations, e.g. amino acids.
What is SGLT2 inhibition?
Tmax can be exploited for therapeutic use.
SGLT2 inhibitors limit Tmax, though not completely due to SGLT1.
This means glucose is excreted at lower concentrations.
Inhibitors are canagliflozin, dapagliflozin.
This is useful in treatment of diabetes mellitus.
What is the movement of amino acids in the proximal tubule?
The concentration of individual amino acids are low, but in the plasma are higher.
Amino acids use many transporters, but mainly cotransporters that use the Na+ gradient.
This is secondary active transport on the apical membrane.
What is Cl- paracellular movement in the proximal tubule?
Cl- moves paracellularly, driven by bulk flow.
When water moves paracellularly, Cl- follows.
As Na+ is moved across, causes a small positive electrical charge, so Cl- also goes across membrane into cortical interstitial space.
What is transcellular movement methods of Cl- in the proximal tubule?
Cl- exchanges with another anion - anion exchangers on apical membrane.
Cl- channels on basolateral membrane.
How does Cl- cross the apical membrane?
Methanoate (HCOO-) is exchange in opposite direction with Cl-.
Methanoate in the filtrate then adds H+ to form methanoic acid, which is uncharged and small, so can easily cross back over the apical membrane.
The Methanoate then cycles back and forth to transport Cl-.
What is active secretion in the proximal tubule?
Organic ions such as drug metabolites are actively secreted in the proximal tubule e.g. penicillin, PAH, furosemide.
The negative charge often comes from carboxylates of sulfonates.
They move from the cortical interstitial space into the filtrate
What are the modes of secretion in the proximal tubule?
On the basolateral membrane there are organic anion transporters (OAT.
On the apical membrane there are multidrug resistance-associated protein (MRP).
What is the process of secretion in the proximal tubule?
The drug metabolite anions are pumped across the basolateral membrane against another anion, usually a-ketoglutarate.
The drug metabolites are then transported by the MRP into the filtrate, against another anion.
Anions can be Cl-, which helps with Cl- reabsorption, or OH-, or HCO3-.
What is the pharmacology of active secretion?
The transport mechanisms in the proximal tubule are a site for drug interaction.
OAT has a maximum rate, so if taking multiple drugs that use OAT for secretion, there will be slower absorption of drugs.
What is the Loop of Henle?
The segment after the Proximal tubule.
The descending limb goes from the cortex (outer layer) into the medulla (inner layer), and the ascending limb goes back to the cortex.
After this is the distal tubule, then the collecting duct.
What is the relationship of the tubules?
Tubules are packed in very close to one another.
Transport from one tubule can affect transport of another tubule.
Descending limb is very close to ascending limb of loop of Henle, so can also affect movement.
What is the thick ascending limb?
Creates a hyperosmolar interstitial space in the medulla to drive water loss from the descending limb and cortical collecting duct.
It does this by pumping salts by active transport into the interstitial space.
What is the descending limb of the loop of henley?
Water moves between the cells (transcellular), as leaky.
Mainly for reabsorption of water, which leaves the filtrate because of osmotic force.
What is movement in the thick ascending limb?
Main cotransporter on the apical surface is NKCC2, which moves Na+, K+ and 2 Cl- into the cell from the filtrate.
Cl- and Na+ are then reabsorbed into the interstitial space, and K+ is recycled, either into the filtrate or interstitial space.
There is no paracellular movement as the tight junctions are tight.
How are Na+ and Cl- reabsorbed in the thick ascending limb?
Cl- is passive diffusion, as 2 are moved in so there is a big electrochemical gradient.
Na+ is pumped out using the Na+/K+ ATPase pump.
What is furosemide?
Furosemide is a diuretic which inhibits Na+ and Cl- reabsorption by blocking the NKCC2 transporter, which stops osmotic gradient building up in medulla, so stops water reabsorption.
Causes diuresis - increase in urine output.
What are the uses of furosemide?
Used for cardiac failure and renal failure
In heart failure, there is a build-up of fluid due to volume overload, so need to remove the extra volume using furosemide.
What are the side effects of furosemide?
Problems with K+ regulation, so causes K+ loss into urine.
K+ is needed for heart function - causes cardiac dysrhythmias, especially if given with digoxin.
Also causes weight chains, metabolic alkalosis, and loss of Mg2+ and Ca2+.
What is Na+ absorption in the distal tubule of the cortex?
Na+/Cl- co-transporter on the apical surface.
Na+ is then reabsorbed using the Na+/K+ ATPase pump.
K+ is pumped out by K+/Cl- co-transporter.
What is Thiazide?
A diuretic which works in the distal tubule by inhibiting the Na+/Cl- co-transporter, so inhibits reabsorption of Na+ and Cl-.
This stops the osmotic gradient and therefore stops water reabsorption.
What are the uses of thiazides?
Thiazides e.g. Bendroflumethiazide and hydrochlorothiazide.
Also thiazide-like drugs e.g. indapamide are diuretics with similar effects.
Act in conjunction with furosemide
What are the side effects of thiazides and like drugs?
Increased uric acid
Hyperglycaemia (high sugar)
Hyponatraemia (low Na+)
What are the collecting ducts?
Collecting ducts are the last place where body can regulate composition of urine - and has the most regulation.
What is the reabsorption of substances in the collecting ducts?
Na+ is mostly reabsorbed by an Na+ channel (not cotransporter), separately controlled..
Collecting duct is key location of K+ secretion.
Regulated by aldosterone
H2O is also regulated, using ADH.
What is spironolactone?
Acts in the collecting tubules and collecting ducts.
It inhibits aldosterone, and acts as a diuretic.
Used in heart failure, as it spares K+.
What are the side effects of spironolactone?
Gynaecomastia, menstrual disorders, testicular atrophy.
Hyperkalaemia (high K+)
What is urea movement?
In the late distal tubule and cortical collecting duct, which is urea impermeable, as water is removed the urea concentration rises.
In the medullary collecting duct the urea diffuses out of the urea permeable tubule.
What is urea cycling?
The nephron cycles urea around a few times before being excreted.
Urea transporters (UT-A1) are inserted into the wall of the collecting duct to allow reabsorption of urea.
This increases the osmolality of the medulla, so water is reabsorbed.
Urea can be cycled a few times through the descending limb before leaving the body or reabsorbed into the circulatory system.
