K3; Tubular Function Flashcards
1
Q
What are the 5 steps of solute reabsorption?
A
- ) Apical/luminal membrane
- ) Cytosol
- ) Basolateral membrane
- ) Interstitial fluid
- ) Capillary wall (endothelium)
2
Q
What is paracellular diffusion?
A
Substances/solutes move into the interstitial fluid between tubular cells down an electrochemical gradient
3
Q
What does transcellular transport entail?
A
- Transport of solute through the cell (apical/cytosol/basolateral)
- Diffusion or active
4
Q
How do hydrophilic molecules cross the membrane?
A
Via channels/carrier or transporter; water soluble/difficult to cross membranes (unlike lipophilic molecules)
5
Q
What is the difference between simple and facilitated diffusion?
A
- Simple; channels/pores through membrane
- Facilitated; carriers (specialised)
6
Q
What is the difference between primary and secondary active transport?
A
- Primary: directly coupled to an energy source (e.g. hydrolysis of ATP)
- Secondary: indirectly coupled to an energy source e.g. using the energy of a molecule moving down its concentration gradient for another to move against
7
Q
What is the transport maximum, Tm?
A
The limit of a particular transporter; capacity of carrier is exceeded e.g. Na+/glucose transporter, plasma glucose is too great = glucosuria
8
Q
Which solutes are typically reabsorbed via passive diffusion?
A
- Cl-
- H2O
- Urea
9
Q
Which solutes are typically reabsorbed via active transport?
A
- Na+
- Ca2+
- Amino acids
- Glucose
- PO43-
10
Q
What is a uniporter?
A
Transporter/carrier transporting one solute across
11
Q
What is an antiporter?
A
A carrier/transporter that moves two solutes across in opposite directions
12
Q
What is a symporter?
A
A carrier/transporter that moves two solutes in the same direction
13
Q
What is Bulk flow?
A
When various constituents/large number of solutes are moved together in bulk
14
Q
Where is the PCT located/what is its shape like?
A
- Continuous with the Bowman’s space of the Bowman’s capsule
- Lies entirely in the cortex
- First part the tubule is highly convoluted
- Second part is straight and leads on to the LoH
15
Q
How are the cells arranged in the PCT and how are they specialised?
A
- Single layer of cuboidal cells which interlock and are connected by tight junctions
- Have large amounts of mitochondria (supplying energy for reabsorption of nutrients, electrolytes etc.)
- Have microvilli; present on the apical/luminal edge (increasing surface area available for reabsorption)
16
Q
What is reabsorbed at the PCT and what is it dependent on?
A
- Na+, Cl-, K+, HCO3, glucose, water, urea, AAs
- Dependent on Na+/K+ ATPase pump
17
Q
What is secreted at the PCT and how?
A
- Organic acids/bases (metabolites etc)
- Drugs e.g. diuretics (how they reach their site of action), penicillins, opioids
- An active process
18
Q
Describe the processes that occur at PCT reabsorption.
A
Na+/K+ ATPase
- 3 Na+ out, 2 K+ in (tubular cell)
- Antiporter
- ATP is hydrolysed (primary active)
- Movement of Na+ against its concentration gradient out of tubular cell
- Interstitial fluid has more salt in than intracellularly
- K+ then just exits back into the interstitial fluid via a channel in the basolateral membrane
- This makes the tubular cell low in Na+ intracellularly
- Allows Na+ reabsorption; moving from the tubular lumen to tubular cell down a concentration gradient via Na+/H+ antiporter
- H+ is secreted into the tubular lumen at the same time via secondary active transport (against its concentration gradient)
- H+ ion that is pumped out is from the dissociation of carbonic acid
- H2O + CO2 in the tubular cell combine with the help of carbonic anhydrase to give carbonic acid
- Rapidly dissociating to give H+ + HCO3- (bicarbonate)
- Meanwhile in the tubular lumen, H+ (from Na+/H+ antiporter) combines with HCO3- to give carbonic acid
- Apical CA allows for dissociation of carbonic acid into H2O + CO2
- Dissolved CO2 diffuses across the apical membrane to contribute to carbonic acid formation in the tubular cell
- This allows for the HCO3- to be reabsorbed into the blood, leaving the tubular cell via the basolateral membrane and across the interstitial fluid
- The other H+ keeps getting cycled around into the tubular lumen and back to the cell
- Apical membrane is impermeable to HCO3- ions hence above
- Na+/glucose symporter (SGLT-2) allows for glucose reabsorption against its concentration gradient (secondary active process) using energy from Na+ diffusion from lumen to cell down its concentration gradient
- Glucose moves into the interstitial fluid and reabsorbed into the blood via glucose carrier in the basolateral membrane
- Na+/AA symporter follows same process
19
Q
What is the journey of Na+ in its active reabsorption in the PCT?
A
- Na+/K+ ATPase pump (carrier) hydrolyses ATP to ADP
- This gives energy for 3 Na+ to be transported out of the tubular cell into the interstitial fluid
20
Q
Where does K+ feature during active reabsorption in the PCT?
A
2 K+ are transported from the interstitial fluid into the tubular cell when 3 Na+ are turned out by the ATPase
21
Q
Where do glucose and AAs feature during active reabsorption in the PCT?
A
Transported by symporters:
- Na+/glucose
- Na+/AAs
22
Q
Where does H+/HCO3- feature during active reabsorption in the PCT?
A
- HCO3- is reabsorbed (via generation of carbonic acid and carbonic anhydrase; apical membrane impermeable to bicarbonates)
- H+ secreted and cycled
23
Q
What is passively reabsorbed in the PCT?
A
- Water
- Ca2+
- Cl-
- K+
- Some Na+
24
Q
How is water absorbed in the PCT?
A
- Osmotic gradient (via Na+ reabsorption, following Na+)
- Primarily through ‘leaky’ tight junctions (paracellular)
- But also via aquaporins (water channels) in the apical and basolateral membranes; transcellular
- Results in high water permeability
25
How are Ca2+, Cl-, K+ and some Na+ absorbed passively?
- Paracellularly through tight junctions
| - As a result of active reabsorption of Na+ at basolateral membrane
26
How much urea is reabsorbed in the PCT and how?
- 50% of urea
- Indirectly linked to Na+ reabsorption
- H2O reabsorbs following Na+, which creates a concentration gradient favouring passive reabsorption of urea
27
What is between the PCT and the DCT?
- Loop of Henle
| - Macula densa
28
What is the difference between the early and late DCT?
Early:
- Reabsorbs Na+, Cl-, K+
- Virtually impermeable to H2O and urea
Late:
- Composed of principal (P) cells and intercalated (I) cells
- P cells; reabsorb Na+ BUT secrete K+ (instead of reabsorbing as in early)
- I cells; reabsorb K+ and HCO3- (role in acid/base balance), secrete H+
29
What transporters are expressed at the early DCT and their functions?
- Na+/K+ ATPase still pumping 3 Na+ out of the tubular cell (against concentration gradient) and 2 K+ in
- Na+/Cl- symporter in apical membrane then allows for Na+ to flow down its concentration gradient into the tubular cell, taking Cl- with it (thus electrically neutral)
- Symporter also target for thiazide diuretics
- Cl- leaves the tubular cell via a simple Cl- channel and is reabsorbed along with the Na+
30
What transporters are expressed in the P Cells of the Late CDT/CD and what is reabsorbed?
- Na+/K+ ATPase still pumping 3 Na+ out of the tubular cell (against concentration gradient) and 2 K+ in
- Allowing for Na+ to be reabsorbed down its concentration gradient via a Na+ selective channel (ENaC) in the apical membrane
- Secretion of K+ (from ATPase pump) via simple K+ channel in the apical membrane, or via simple K+ channel in basolateral membrane (goes to lumen AND interstitial fluid)
31
What hormones and drugs are the P cell a site of action for?
- Aldosterone
- Antidiuretic hormone (ADH)
- ENaC is target for amiloride (diuretic)
32
How does aldosterone work?
- Increases Na+ (and thus water reabsorption) with accompanying K+ excretion
- Upregulates gene expression of epithelial Na+ selective channels (ENaC) and Na+/K+ ATPase transporters
- More of these proteins are thus present allowing increased Na+ reabsorption and thus water etc
- Also increases H+ secretion in I-cells
33
What is aldosterones route from secretion to target?
- Made in the adrenal cortex
- Secretion stimulated by Ang II (RAAS pathway)
- Also stimulated by high [K+]
- And ACTH from the anterior pituitary (but not as much)
- Lipophilic (crossing membranes easily); target is an intracellular receptor - the mineralocorticoid receptor
- Activation of mineralocorticoid receptor results in translocation of it into the nucleus, switching on gene transcription factors and subsequent translation
- Thus leading to an increase in aldosterone-induced proteins (ENaC = Epithelial Na+ Channel and Na+/K+ ATPase)
- Aldosterone also has activity on plasma membrane receptor which bring about a more rapid effect (non-genomic effect vs. genomic effect on gene transcription earlier)
34
What is renin release stimulated by?
- Low [NaCl] at macula densa cells (low body fluid osmalility)
- Low BP; baroreceptors in afferent arterioles
- β-adrenoceptors; sympathetic NS
35
What does renin do?
- Renin is released from granular cells at the afferent arteriole
- Increases Ang II and aldosterone release
- Increases Na+ reabsorption and thus H2O retention
- Restores parameters to normal levels:
- Low blood volume/pressure (water/Na+)
- Low body fluid osmolality (water)
36
What is the RAAS pathway?
- Liver produces angiotensinogen
- Converted by renin (from granular cells in the kidney) to give angiotensin I
- ACE (angiotensin converting enzyme) in lungs converts Ang I to Ang II
- Ang II stimulates release of aldosterone from the adrenal cortex (whilst having own activity too; PCT)
- Acts on the kidney (DCT/CD), increasing expression of ENac and ATPase
- Increases Na+ reabsorption leading to accompanying H2O reabsorption and K+ excretion
- Ang II causes vasoconstriction in the PCT of efferent arteriole
37
What is ADH also known as?
Vasopressin (AVP); vasoconstrictor action
38
Where is ADH/AVP synthesised and consequently stored?
- Synthesised in neuroendicrine cells with cell bodies in the hypothalamus
- These hormones are then transported down the axon and stored in nerve terminals in the posterior pituitary
39
How is ADH release stimulated?
- Increase in body fluid osmolality (osmotic control)
- Fall in blood volume/pressure (haemodynamic control)
- Angiotensin II
- Nausea
- Acute stress
40
What are the actions of AVP/ADH?
- Blood vessels; at higher [ADH] it acts on V1 receptors causing vasoconstriction
- Kidney (late DCT/CD); increases water permeability and hence re-absorption of water via V2 receptors
41
How does ADH work at the kidney?
- ADH binds to V2 receptor on basolateral membrane
- V2 receptor is a Gs-coupled receptor, thus activating adenyl cyclase, leading to an increase in cAMP (from ATP); activates protein kinase A (PKA)
- Active PKA phosphorylates certain proteins
- Leads to translocation to the apical membrane of vesicles in the cytosol containing water channels
- Vesicles fuse with the cell membrane
- Insertion of aquaporin 2 (AQP2) water channels in the apical membrane complete (increasing water permeability)
42
Which aquaporins do ADH affect?
- Only promotes the insertion of AQP2 to the apical membrane
| - AQP3 & 4 present in the basolateral membrane but not affected
43
What other effects do ADH have in the collecting duct?
- Causes phosphorylation of UT-A urea transporters
- Leading to increased permeability to urea
- This helps maintain osmolality between interstitial fluid and the tubular lumen (due to increased H2O reabsorption)
44
What role do I cells play in the late DCT/CD and how does it differ to P cells?
- Principle role in acid-base balance
- HCO3- reabsorbed as per PCT (formation of H2CO3 etc)
- H+ ATPase (primary active; hydrolysis of ATP) uniporter moves H+ out of the tubular cell and into the lumen; secretion of H+
- H+ is cycled back once again combining with HCO3- in ultrafiltrate, forming H2CO3, dissociating to H2O and CO2 via apical CA (dissolved CO2 cycles back into tubular cell)
- K+/H+ ATPase antiporter yields K+ reabsorption whilst secreting H+ into the tubular lumen
45
How does aldosterone affect I Cells of the late DCT/CD and how does this differ to P cells?
- Stimulates H+ secretion via plasma membrane receptors
| - P cells bring about a genomic effect via mineralocorticoid receptors to upregulate ENaC and ATPase expression
46
Where is the main site of reabsorption in the kidney?
- PCT (65%+ of Na+/K+/HCO3-/Ca2+/PO43-) as well as Mg2+, H2O, Cl-, urea, glucose, AAs etc.
- DCT plays much smaller role (5-10%)
- CD smaller role still
47
What is the fate of Na+ in the kidney?
- 65% reabsorption at the PCT
- 25% at LoH
- 5% at DCT and CD collectively
-
48
What is the fate of K+ in an individual with low intake?
- Mirrors Na+ reabsorption at low intake; 65% reabsorption at PCT, 20% LoH, 5% DCT/CD respectively
-
49
What is the fate of K+ in an individual with normal-high intake?
- Later segments of the nephron (DCT/CD) have ability to secrete K+ from blood to lumen
- Can excrete K+ from body if required (15-80% secretion)
- 65% reabsorption at PCT, 20% LoH, 5% DCT/CD respectively
50
What is the fate of HCO3- in the kidney?
- 0% excretion
- Bicarbonate required for acid/base balance
- E.g. acidosis = secrete more H+ in urine, alklalosis = reabsorb more H+/respiratory compensation
- 80% reabsorption at PCT, 10% at LoH, 5% DCT/CD respectively
51
What is the fate of glucose in the nephron?
- 0% excreted in healthy individual
- Required for energy; excess stored as fat or glycogen
- 98% reabsorption in PCT, 2% in rest of nephron
52
What is the fate of glucose if an individual has plasma [glucose] > 10mM?
- Exceed capacity for SGLT-2 etc for reuptake of glucose
- Glycosuria ensues; not able to reabsorb all glucose load
- Tm for glucose reabsorption exceeded
