Tubular Function Flashcards
Introduction
The kidney is a central regulator of homeostasis. On an average day we consume 20-25% more water and salts than we need to. Thus in order to maintain homeostasis, we need to los this excess as well as other waste products e.g. urea.
However too much water + small molecules are able to pass through the fenestrae of the glomerular capillaries, thus in order to remove excess/waste whilst retaining “good stuff” – glomerular filtration is followed by controlled reabsorption + secretion. This results in a final urine production which is associated with maintenance of solute balance, plasma concentration + pH.
In reality, 99% of the ultrafiltrate is reabsorbed into the peritubular capillaries.
Define Osmolarity
REMEMBER= IT IS DEPENDANT ON THE NUMBER OF PARTICLES IN A SOLUTION NOT THE NATURE OF PARTICLES
What is the amount of solutes recirculated equal to?
What is the amount of solutes excreted equal to?
amount of solutes recirculated= Amount not filtered + amount reabsorbed - the amount secreted
The amount of solute reciculated= The amount filtered + the amount secreted - the amount reabsorbed
What is the minimum and maximum urine osmolarity in humans?
Urine osmolarity = 50 – 1200 mosmol/l
Draw a diagram showing the renal wall and its associated structures. Also in the diagram illustrate what paracellular and transcellular transport is?
So where does this all take place? The answer is across the renal tubular walls. These walls are made up from a single layer of epithelial cells that separates the tubular fluid from the blood in the peritubular capillaries. These cells are separated by tight junctions which contain specific proteins that allow the movement of some but not all molecules across.
Example
In what direction and from what structures does reabsorption and secretion occur?
Reabsorption occurs in an apical-basal direction (from tubular fluid in lumen to peritubular capillary)
o Secretion occurs in a basal-apical direction (from peritubular capillary to tubular fluid in lumen)
List the 6 types of transport in the tubules?
What type of molecules are transported passively and have a protein independant mechanism of transport?
What type of molecules are transported passively and have a protein dependant mechanism of transport?
AS SOON IT IS DEPENDANT ON A PROTEIN IT WILL HAVE A MAXIMUM RATE
Active movement – Cellular Energy dependent
Draw a diagram showing active transport which is Indirectly coupled to ATP hydrolysis
Directly coupled to ATP hydrolysis, i.e. substance is moved into the cell using the energy from ATP hydrolysis (usually occurs at apical membrane) o Indirectly coupled to ATP hydrolysis, i.e. the substance is moved out of the cell using the energy from ATP hydrolysis (at basal membrane), and this creates a concentration which causes passive movement of the substance into the cell at the apical membrane
Water “pumps” do not exist, therefore transcellular movement of water to an area of high osmolarity is via aquaporins, or water can move across the tight junctions (paracellular movement)
Regulation of a passive uptake system?
If there is a high concentration of an extracellular ion, but there is only one transport ion. The cell will respond by placing more transport proteins on the surface of the cell.
Describe protein trasnport from the tubular fluid to inside the tubular cell?
Proteins Transport
There are low affinity carriers which bind to proteins in the tbular fluid. They will then get endocytosed. That vesicle will the sperate- the cargo will be in one vesicle and the receptor will go back to the surface.
Carrier proteins have a “transport maxima” which influences the max rate of the transport of the solute. However this transport maxima is sufficient so that in a biological system, the transport system is rarely overloaded
o Clinical correlation – glycosuria: the transport system for the reabsorption of glucose is overloaded, thus not all the glucose is reabsorbed from the tubular fluid + some is excreted in the urine
NB: Secretion – mechanism by which substances move from the peritubular capillaries into the tubular fluid (may be passively or actively transported). The most important ions which are secreted are H+ and K+. choline, creatinine, penicillin + other drugs are also secreted, and thus excreted in the urine.
Summary
List some substanes that are secreted into the tubular fluid?
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)
Where does most reabsorption occur?
Regional specification of the nephron tubules
Reabsorption is not uniform
Most reabsorption (60-70%) occurs in the proximal convoluted tubule. This includes:
100% glucose, amino acids + nutrients 65% sodium 90% bicarbonate
o Water + anions then follow along a concentration/electrochemical gradient (maintaining plasma osmolarity)
More ion reabsorption occurs in the loop of Henle (i.e. 25% Na). However only the descending limb of the loop is permeable to water; therefore as tubular fluid moves through the loop, the osmolarity of the urine decreases
. In the early distal convolutes tubule, further ion reabsorption + water transport occurs (8% Na)
The late distal convoluted tubule + renal collecting duct as the final regulators. Variable reabsorption + secretion occurs depending on the body’s needs. This is regulated by aldosterone + vasopressin (ADH)
Cells of the different regions of the nephron tubules thus vary (suited to function)
o Lots of mitochondria are present in the PCT, ascending loop of Henle, + early DCT – indicates lots of active transport occurring
o Large brush border present on all regions except the collecting duct; large surface area means more interaction with tubular fluid = more passive reabsorption
The basolateral sodium and pottasium pumps create a low intercellular sodium concentration. This means that Na+ entry down a large electrochemical gradient can bring about the “uphill” entry of glucose and a-a’s and exit of H+.
The basolateral sodium and pottasium pumps create a low intercellular sodium concentration. This means that Na+ entry down a large electrochemical gradient can bring about the “uphill” entry of glucose and a-a’s and exit of H+.
How does Carbonic anhydrase activity leads to Na+ re-absorption and increased urinary acidity?
Carbonic anhydrase provides H+ which can be used in the antiporter to transport sodium into the cell.
Also Carbonic anhydrase can convert H2CO3 back into water and CO2 . These then passively diffuse back into the proximal tubule cell and and combine to for H2CO3 again in the presence of carbonic anhydrase. The H2CO3 dissociates into H+ and HCO3- which diffuses out of the into the peritubular cappilaries. The H+ diffuses back into the tubular fluid via the antiporter.
What is passively reabsorbed in the PCT?
Proximal convoluted tubule (2)
Passive reabsorption:
Urea and water
Active reabsorption (i.e.: require ATP and carriers):
Glucose
Amino-acids
Sodium
Potassium
Calcium
Vitamin C
Uric acid
Reabsorption of all solutes/water is sensitive to metabolic poisons
The proximal convoluted tubule
Site of most reabsorption, including Na+, Cl-, amino acids, glucose, proteins, water, urea, uric acid, vitamins, lactic acid, K+, Mg2+ o H+ is also secreted
o Creatinine, sulfates, phsophates + nitrates are not reabsorbed, and continue in the the tubular fluid
NB: reabsorption of proteins – involves binding of the proteins on protein-receptors on the apical membrane, formation of pit + internalisation of the proteinreceptor complex into a vesicle. The receptor then dissociates + is recycles; proteins are then broken down into amino acids before transport into the blood
the majority of reabsorption that occurs in the PCT is driven indirectly by the Na/K pump present on the basolateral membrane. This pumps Na+ out of the cell into the peritubular capillary, therefore keeping intracellular [Na] low and [K] high (the cell is also then negative electrochemical gradient)
the concentration + electrical gradients thus favour Na movement ito the cell, and this movement couples the uphill movement of glucose + amino acid into the cell (involving symporter proteins) and H+ out of the cell (involving antiporter carriers)
urea + water then follows passively
PCT reabsorption thus occurs vie indirect ATP hydrolysis (driven by the Na/K pump) – this is used to reabsorb glucose, amino acids, sodium, potassium, calcium, vitamin C + uric acid
The fact the reabsorption is dependent on the Na/K pump – means the reabsorption of all solutes/water are sensitive to metabolic poisons
Secretion – there is some secretion in the PCT, which is important for the excretion of some drugs, as well as the movement of some drugs to more distal parts of the nephron to act there.
Secretion in the PCT
Loop of Henle
The loop can be divided into the descending and ascending limb
The descending limb is ……………, and highly permeable to …………… (which is passively reabsorbed between the squamous epithelium)
o There are few …………… in the descending limb as ions are not actively transported
The ascending limb is …………… and more involved in ion transport, therefore contains many more …………….
o Consists of a …………… epithelium with few microvilli, but is impermeable to ……………
What do loop diuretucs block?
Loop of Henle
The loop can be divided into the descending and ascending limb
The descending limb is ……………, and highly permeable to …………… (which is passively reabsorbed between the squamous epithelium)
o There are few …………… in the descending limb as ions are not actively transported
The ascending limb is …………… and more involved in ion transport, therefore contains many more …………….
o Consists of a …………… epithelium with few microvilli, but is impermeable to ……………
o Again, the Na/K pump on the basal membrane creates a concentration + electrical gradient, which drives the symporter on the apical membrane. This symporter transports 1 Na, 1 K and 2 Cl ions into the cell (making the inside of the cell negative compared to the outside)
o However, there is also a K+ channel on the apical membrane which allows K+ to leak into the lumen along its concentration gradient. However this exaggerates the electrical gradient thus driving paracellular movement of the cations Na, K, Ca + Mg
o Loop diuretics block the Na/K/Cl co-transporter
On leaving the loop, 85% water + 90% of Na and K have been reabsorbed. However the fact that the ascending limb is impermeable to water means the tubular fluid is also hypo-osmolar compared to the plasma
Describe the epithelium of the ascending and descending epithelium?
Proximal part of distal convoluted tubule
…………….. epithelium, few ……………..
Complex lateral membrane interdigitations with Na+ pumps
Numerous large ……………..
Na+ and Cl- co-transporter linked to …………….. reabsorption
Na+ and chloride are reabsorbed by a channel sensitive to …………….. (…………….. cause a rise in plasma Ca2+)
Proximal part of distal convoluted tubule
Cuboidal epithelium, few microvilli
Complex lateral membrane interdigitations with Na+ pumps
Numerous large mitochondria
Na+ and Cl- co-transporter linked to Ca2+ reabsorption
Na+ and chloride are reabsorbed by a channel sensitive to thiazides. (Thiazides cause a rise in plasma Ca2+)
There is also a specialisation of the DCT where it meets the glomerulus = macula densa (forms part of juxtaglomerular apparatus) – detects changes in the [Na] of the tubular fluid filtrate
What happens in the distal dct and the cortical collecting duct?
What type of control is regulation under?
What two type of cells do they consist of ?
What are Intercelated cells important for?
The principle cells of the DCT are under the control of ………………….., whereas the principle cells of the cortical collecting duct are under the control of …………………..
What are principle cells important for?
The principal cells of the cortical collecting duct have a ………….. …………….., therefore tightly regulate water movement (driven by osmolarity gradient)
The Distal DCT + Cortical Collecting duct
“fine” tuning of the filtrate in order to maintain homeostasis (plasma osmolarity, pH etc) occurs here
Regulation is under hormonal control (aldosterone + ADH/Vasopressin)
Consist of two types of cells: principle cells + intercalated cells
The principle cells of the DCT are under the control of aldosterone, whereas the principle cells of the cortical collecting duct are under the control of ADH/Vasopressin
Principle cells are important in sodium, potassium + water balance (mediated via Na+/K+ pump on basolateral membrane).
In the principle cells of the DTC, the apical sodium channel is sensitive to aldosterone, and is linked to a K+ channel also on the apical membrane
Intercalated cells exist between each principle cell, and are important in acid-base balance, mediated by an HATP pump on the apical membrane
The principal cells of the cortical collecting duct have a tight epithelium, therefore tightly regulate water movement (driven by osmolarity gradient)
What are priniciple and intercelated cells important for?
Principal Cell: important in sodium, potassium and water balance (mediated via Na/K ATP pump)
Intercalated Cell: important in acid-base balance (mediate via H-ATP pump)
Single gene defects that affect tubular function
name 3
Renal tubule acidosis
Bartter syndrome
Fanconi syndrome- (Dent’s disease)
What is renal tubular acidosis?
failure of H+ secretion has 2 possible causes: name them
Renal tubular acidosis
Caused by an inability to acidify the urine below pH5.5
hypechloremic metabolic acidosis of the blood
Other symptoms include impaired growth + hypokalemia
Mainly a defect in the distal renal tubule
failure of H+ ion secretion even when conditions are favourable for secretion
In a normal tubular cell, H+ secretion occurs simultaneously to HCO3 - transport out of the cell into the blood. This is driven by a reaction catalysed by carbonic anhydrase.
failure of H+ secretion has 2 possible causes:
malfunction of bicarbonate transport out of tubular cell into blood
accumulation of product therefore limiting carbonic anhydrase activity.
A mutation in the carbonic anhydrase enzyme could also occur
What is bartter syndrome and what causes it?
Bartter syndrome
Definition = excessive electrolyte secretion
Caused by mutation in the Na/Cl/K co-transporter on ascending limb of Henle, or mutation in the K+ channel
Causes severe salt loss, moderate metabolic alkalosis, hypokalemia, renin + aldosterone hypersecretion
Antenatal barter syndrome = more severe form of disease
premature birth +polyhydramnios
What is Fanconi’s syndrome?
Fanconi Syndrome
Defined by an increased excretion of low molecular weight proteins caused by a failure of protein reabsorption
Also increased excretion of uric acid + glucose phosphate
Caused by a defect in a Cl- channel involved in protein-receptor vesicle recycling
reduction of protein receptors therefore proteins cannot be reabsorbed
E.g. of detrimental consequence = excessive amounts of cytokines flowing through tubular system
immune response
FOCUS ON THE WAY THIAZIDE DRUGS WORK
Look at his questions at end of panopto
Look at his questions at end of panopto
