Tubular Function Flashcards
Essentially, what is the kidney
The kidney is a central regulator of homeostasis
What is the problem that the kidney has to solve
How to get rid of stuff I’ve taken in but don’t want to keep, but to keep enough of what we want
Where are things to be excreted taken to
The bladder ( excess water, Na+, and urea)
On an average day, what do we consume
On an average day we consume more water and salt than we need to replace that ‘used up’.
We need to lose this and other waste products (e.g. urea)
Do we have pumps for water
No, therefore we have to continuously filter stuff
How do we produce urine
We produce urine by passive filtration, through a molecular sieve (glomerular filtration)
BUT
Can’t afford to lose all of the water and small molecules that pass through the filter
Therefore, we reabsorb some substances back into the blood
Describe controlled reabsorption and secretion
§ We need to reabsorb 99% of the filtrate (70% is done in the PCT).
§ We also need to maintain solute balance, plasma concentration and pH.
Define osmolarity
“a measure of the osmotic pressure exerted by a solution across a perfect semi-permeable membrane”
What does osmolarity depend on and how do we calculate it
Dependent on the number of particles in a solution and NOT the nature of the particles
All the concentrations of the different solutes (measured in mmol/l) added together. Each ion is “counted” separately
Describe the range for normal plasma osmolarity
SMALL plasma variation in osmolarity = 285-295mosmol.L-1.
· Sodium = ~140mmol.L-1.
· Chloride = ~105mmol.L-1.
Describe urine osmolarity
LARGE urine variation in osmolarity = 50-1200mosmol.L-1.
· Sodium = ~50-200mmol.L-1.
· Potassium = ~40-100mmol.L-1.
Essentially, how do we maintain plasma osmolarity
Monitor and change urine osmolarity
Any solute present at equal concentrations either side of a semi-permeable membrane can have no net effect on water movement
Describe the tubular fluid
present within the tubules, produced from ultrafiltration of blood; contains glucose, small proteins, urea, electrolytes, water and other molecules filtered from the blood
Describe the luminal membrane
faces the lumen and contains many co-transporters that use sodium to facilitate reabsorption of key substances such as glucose (and antiporters for protons) as well as aquaporins for water
Describe the basolateral membrane
contains protein channels to allow specific molecules to cross the membrane and enter the peritubular capillaries, as well as Na+/K+-ATPase pumps and a Cl-/HCO3- exchanger
Describe the peritubular capillaries
run alongside the epithelial cells
Describe the tight junctions
join the epithelial cells; allow passage of K+/Mg2+/Cl-/H2O/urea via transcellular route
Describe the role of the Na+/K+ ATPase
actively exchanges 3 Na+ in the lining for 2 K+ in the blood to establish a concentration gradient for co-transport of molecules
Summarise transport in the renal tubular wall
§ Transcellular is much more tightly regulated than the paracellular pathway.
§ Note the 2 forms of reabsorption and secretion (trans- and paracellular)
§ Forms of transport include:
o Osmosis.
o Active transport.
o Counter transport.
o Co-transport.
o Passive transport.
o Movement down electrochemical gradient.
Describe the movement of lipophilic molecules
Protein independent transport (lipophilic molecules
Pass through the cell membrane
Rate is directly proportional to the solute concentration
Describe the movement of hydrophilic molecules
Protein dependent transport (hydrophilic molecules)
rate not directly proportional to solute concentration- plateaus at a certain solute conc as the rate is limited by the availability of membrane transporters (carrier or channel protein)
Describe active movement in the renal tubules
§ Active movement can be:
o Directly coupled to ATP hydrolysis – Primary Active Transport.
§ E.G. Vitamins, Ca2+ transport.
o Indirectly coupled to ATP hydrolysis – Secondary Active Transport.
§ Na+/K+ATPase – Counter-transport.
§ Na+/Glucose, Cl-, aa – Co-transport.
What is ATP needed for in secondary active transport
ATP used to establish concentration gradient for symport/antiport
Describe water transport in the renal tubules
can move through tight junctions and via aquaporins on cell surface membranes (low to high osmolarity
How can we regulate the rate of passive transport
§ The regulation of this passive uptake can then be controlled by storing the channel proteins in vesicles and releasing them as required to the membrane (to increase the rate of uptake).
Describe protein reabsorption in the renal tubules
some protein does enter primary urine; receptors on tubular wall have low specificity and high affinity, leading to endocytosis to vesicle; endosome pH decreases, leading to detachment and recirculation of receptors to membrane
Describe transport maxima
§ Systems may be regulated and so may have a basal AND stimulated maxima rate of absorption.
§ However, systems may also only have one state of rate reabsorption.
Describe what happens in excess glucose levels
Filtration proportional to plasma conc of glucose
Normally, we reabsorb all of the glucose filtered
However, after a certain conc (10-15mmol/L)
the protein channels are all saturated so the rate plateaus. We therefore start seeing glucose in the urine at a conc proportional to the conc in the plasma past the threshold for its reabsorption
When is glycosuria seen
Seen in Diabetes Mellitus and ingestion of large quantities of vitamins.
Are transporters expressed uniformly across the length of the nephron
Transporters are located in different parts of the nephron. Most of the Na transporters are located in the proximal tubule, while fewer are spread out through other segments.
What does the concentration of urine produced depend on
depends on level of ADH which controls collecting duct permeability (as affects volume of water reabsorbed)
Describe secretion
Moves substances from peritubular capillaries into tubular lumen
Like filtration, this constitutes a pathway into the tubule
Can occur by diffusion or by transcellular mediated transport
The most important substances secreted are H+ and K+
Choline, creatinine, penicillin & other drugs also secreted
Active secretion from blood side into tubular cell (via basolateral membrane) and from cell into lumen (via luminal membrane)
Summarise reabsorption in the PCT
60-70% of all solute 100% glucose 65% Na 90% bicarb Water and anions follow Na+ (osmolarity is maintained)
Summarise reabsorption in the loop of Henlé
Concentration of urine
25% Na
Summarise reabsorption in the DCT
Distal Convoluted tubule
8% Na
Summarise reabsorption in the collecting duct
Variable absorption regulated by aldosterone and vasopressin
Most tightly regulated part of the nephron
Summarise the histology of each region
§ PCT – ciliated, highly metabolically active so lots of mitochondria.
§ LoH thin descending limb – no ciliated surface, not much metabolic action.
§ LoH thick ascending limb – no ciliated surface, LOTS of mitochondria as metabolic action.
§ DCT – ciliated surface (not as much as proximal) and some mitochondria as some reabsorption still (sodium).
§ Collecting duct – no cilia, not as much mitochondria as has a more modulatory role.
Describe the role of the Na+/K+ ATPase in the basolateral cell membrane of the PCT
Na/K pump keeps intracellular [Na] low and [K] high
Large conc. and electrical gradients favour Na movement into the cell (occurs in most nephron segments
Na+ entry down a large electrochemical gradient can bring about the “uphill” entry of glucose and a-a’s and exit of H+
potassium, calcium and vitamins are also co-transported
Describe how the reabsorption of Na+ can lead to the indirect reabsorption of bicarbonate
Na+ exchanged for H+
H+ buffers bicarbonate in the tubular fluid to make carbonic acid, which is broken down (by carbonic anhydrase) into CO2 and H20
CO2 and H2O enter the cell, where carbonic anhydrase acts on it to reform bicarbonate and H+
H+ exchanged for Na+ and HCO3- moves into blood down electrochemical gradient
What is passively reabsorbed in the PCT
Urea and water
What is actively reabsorbed in the PCT
Glucose Amino-acids Sodium Potassium Calcium Vitamin C Uric acid Reabsorption of all solutes/water is sensitive to metabolic poisons
Describe secretion in the PCT
There is net secretion by the PCT.
Important because:
-it is a route of excretion for some substances
some drugs enter the tubular fluid here and act further down the nephron.
How much sodium do we need to reabsorb and how can this vary
99% + or - a small amount depending on the regulation of the collecting duct
Describe what happens in the descending limb
squamous epithelium with few mitochondria
Water passively reabsorbed; Draws in Sodium and Potassium
Describe what happens in the ascending limb
Cuboidal epithelium, few microvilli but many mitochondria
Chloride actively reabsorbed
Sodium passively reabsorbed with it
Bicarbonate reabsorbed
Impermeable to water
Describe the properties of the fluid leaving the ascending limb
By now 85% water and 90% sodium and potassium have been reabsorbed.
Tubular fluid leaving the loop of Henle is hypo-osmolar with respect to plasma
Describe how the ascending limb of the loop of Henlé achieves its function
Na+/K+ ATPase in the basolateral cell membrane maintains low conc of Na+ inside cell
2CL- actively reabsorbed from lumen (with Na+ and K+ moving in passively)- K+ gradient maintained by K+ channel in apical membrane
CL- symport with K+ in basolateral cell membrane- can also move passively through its own channel
Ca2+, Mg2+, Na+ and K+ can also move paracellularly into the blood
Explain how the fluid leaving the ascending limb is hypo-osmolar
PCT- Isoosmolar
85% water and 90% sodium and potassium have been reabsorbed
More salt than water has been reabsorbed
Tubular fluid leaving the loop of Henle is hypo-osmolar with respect to plasma
Describe the characteristics of the proximal part of the DCT
Cuboidal epithelium, few microvilli
Complex lateral membrane interdigitations with Na+ pumps
Numerous large mitochondria
Describe how the proximal part of the DCT achieves its function
Na+/K+ ATPase in basolateral cell membrane maintains low Na+ conc, allowing for its co-transport with Cl- into the cell from the lumen, this also drives the movement of Ca2+ into the cell through a separate channel
Cl- enters the blood passively
3Na+ exchanged for Ca2+ in basolateral cell membrane
Describe the actions of Thiazides
Na+ and chloride are reabsorbed by a channel sensitive to thiazides. (Thiazides cause a rise in plasma Ca2+)
Na+ can only enter through basolateral Na+/Ca2+ antiporter- so this works faster- increasing the reabsorption of Ca2+
Describe the specialisation of the DCT
Specialisation at macula densa, part of juxtaglomerular apparatus – detects changes in [Na+] of filtrate
Describe the roles of the distal DCT and collecting duct
Fine’ tuning of the filtrate to maintain homeostasis
DCT – Sodium reabsorbed
(dependent on aldosterone).
CT – Sodium reabsorbed
(dependent on aldosterone).
Adjustment of Na+/K+/H+/NH4+
Water reabsorbed under control of ADH.
What is the default state of the distal part of the nephron
Distal part of nephron is impermeable to water without ADH.
What features of the distal DCT and collecting duct allow it to be regulated
Involving: (i) An apical Sodium channel sensitive to aldosterone
(ii) Linked K+ channel (iii) pH control
Describe the role of the principal cell
important in sodium, potassium and water balance (mediated via Na/K ATP pump)
Aldosterone causes Na+ reabsorption, which kicks out K+ via a separate channel
Na+/K+ ATPase in basolateral cell membrane
K+ coming in can also move out via a different channel
Cl- will also move paracellularly
Describe the intercalated cell
important in acid-base balance (mediate via H-ATP pump- apical membrane)
HCO3- exchanged for CL- on basolateral cell membrane
Describe the principal cell in the cortical collecting duct
Very “TIGHT” epithelium: very little paracellular transport
ADH causes water reabsorption from the lumen and movement of Na+ from the cell to the blood- where water moves with it
List the single gene defects that effect tubular function
Renal tubule acidosis
Bartter syndrome
Fanconi syndrome
(Dent’s disease)
What are the features of renal tubular acidosis
hyperchloremic metabolic acidosis
impaired growth
hypokalemia
What is the defect in renal tubular acidosis
monogenic mutation leading to failure to secrete protons or faulty carbonic anhydrase leads to accumulation in blood
protons LEAK BACK INTO the cell after being pumped out into the lumen and so your urine becomes alkaloid.
May not be reabsorbing HCO3-
Describe the features of Bartter syndrome
Excessive electrolyte secretion Antenatal Bartter syndrome Premature birth, polyhydramnios severe salt loss moderate metabolic alkalosis hypokalemia renin and aldosterone hypersecretion
What is the defect in Bartter Syndrome
mutation in the Na+/Cl-/K+ cotransporter means it is no longer functional
What are the features of Fanconi syndrome
Increased excretion of uric acid, glucose, phosphate, bicarbonate
Increased excretion of low MW protein
Disease of the proximal tubules associated with Renal tubular acidosis (type 1)
What is the defect in Fanconi syndrome
§ Disease in the proximal tubules.
§ Otherwise known as Renal Tubular Acidosis: Type 1 – DENT’S DISEASE – CIC-5 mutation.
o In receptor-mediated endocytosis, a proton pump is required to dissociate the protein from the receptor but one of these is mutated.
o Too many protons inside endosome so receptor never dissociates.
What should happen in the endosome
Pump protons in the endosome to allow dissociation of protein from receptor
As +ve charge accumulates it gets harder to pump protons in
So we have a transporter to exchange protons out for 2CL-, losing charge, without pH and allowing protons in- net reduction of -3 in charge
This is mutated in Fanconi syndrome- can’t recirculate receptor- therefore protein is excreted
