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RED - Kidney Pharmacology & Therapeutics > K3; Tubular Function > Flashcards

K3; Tubular Function Flashcards

1
Q

What are the 5 steps of solute reabsorption?

A
  1. ) Apical/luminal membrane
  2. ) Cytosol
  3. ) Basolateral membrane
  4. ) Interstitial fluid
  5. ) Capillary wall (endothelium)
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2
Q

What is paracellular diffusion?

A

Substances/solutes move into the interstitial fluid between tubular cells down an electrochemical gradient

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3
Q

What does transcellular transport entail?

A
  • Transport of solute through the cell (apical/cytosol/basolateral)
  • Diffusion or active
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4
Q

How do hydrophilic molecules cross the membrane?

A

Via channels/carrier or transporter; water soluble/difficult to cross membranes (unlike lipophilic molecules)

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5
Q

What is the difference between simple and facilitated diffusion?

A
  • Simple; channels/pores through membrane

- Facilitated; carriers (specialised)

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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
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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

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8
Q

Which solutes are typically reabsorbed via passive diffusion?

A
  • Cl-
  • H2O
  • Urea
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9
Q

Which solutes are typically reabsorbed via active transport?

A
  • Na+
  • Ca2+
  • Amino acids
  • Glucose
  • PO43-
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10
Q

What is a uniporter?

A

Transporter/carrier transporting one solute across

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11
Q

What is an antiporter?

A

A carrier/transporter that moves two solutes across in opposite directions

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12
Q

What is a symporter?

A

A carrier/transporter that moves two solutes in the same direction

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13
Q

What is Bulk flow?

A

When various constituents/large number of solutes are moved together in bulk

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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
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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)
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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

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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
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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
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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

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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

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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
Q

How are Ca2+, Cl-, K+ and some Na+ absorbed passively?

A
  • Paracellularly through tight junctions

- As a result of active reabsorption of Na+ at basolateral membrane

26
Q

How much urea is reabsorbed in the PCT and how?

A
  • 50% of urea
  • Indirectly linked to Na+ reabsorption
  • H2O reabsorbs following Na+, which creates a concentration gradient favouring passive reabsorption of urea
27
Q

What is between the PCT and the DCT?

A
  • Loop of Henle

- Macula densa

28
Q

What is the difference between the early and late DCT?

A

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
Q

What transporters are expressed at the early DCT and their functions?

A
  • 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
Q

What transporters are expressed in the P Cells of the Late CDT/CD and what is reabsorbed?

A
  • 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
Q

What hormones and drugs are the P cell a site of action for?

A
  • Aldosterone
  • Antidiuretic hormone (ADH)
  • ENaC is target for amiloride (diuretic)
32
Q

How does aldosterone work?

A
  • 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
Q

What is aldosterones route from secretion to target?

A
  • 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
Q

What is renin release stimulated by?

A
  • Low [NaCl] at macula densa cells (low body fluid osmalility)
  • Low BP; baroreceptors in afferent arterioles
  • β-adrenoceptors; sympathetic NS
35
Q

What does renin do?

A
  • 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
Q

What is the RAAS pathway?

A
  • 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
Q

What is ADH also known as?

A

Vasopressin (AVP); vasoconstrictor action

38
Q

Where is ADH/AVP synthesised and consequently stored?

A
  • 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
Q

How is ADH release stimulated?

A
  • Increase in body fluid osmolality (osmotic control)
  • Fall in blood volume/pressure (haemodynamic control)
  • Angiotensin II
  • Nausea
  • Acute stress
40
Q

What are the actions of AVP/ADH?

A
  • 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
Q

How does ADH work at the kidney?

A
  • 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
Q

Which aquaporins do ADH affect?

A
  • Only promotes the insertion of AQP2 to the apical membrane

- AQP3 & 4 present in the basolateral membrane but not affected

43
Q

What other effects do ADH have in the collecting duct?

A
  • 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
Q

What role do I cells play in the late DCT/CD and how does it differ to P cells?

A
  • 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
Q

How does aldosterone affect I Cells of the late DCT/CD and how does this differ to P cells?

A
  • Stimulates H+ secretion via plasma membrane receptors

- P cells bring about a genomic effect via mineralocorticoid receptors to upregulate ENaC and ATPase expression

46
Q

Where is the main site of reabsorption in the kidney?

A
  • 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
Q

What is the fate of Na+ in the kidney?

A
  • 65% reabsorption at the PCT
  • 25% at LoH
  • ## 5% at DCT and CD collectively
48
Q

What is the fate of K+ in an individual with low intake?

A
  • ## Mirrors Na+ reabsorption at low intake; 65% reabsorption at PCT, 20% LoH, 5% DCT/CD respectively
49
Q

What is the fate of K+ in an individual with normal-high intake?

A
  • 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
Q

What is the fate of HCO3- in the kidney?

A
  • 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
Q

What is the fate of glucose in the nephron?

A
  • 0% excreted in healthy individual
  • Required for energy; excess stored as fat or glycogen
  • 98% reabsorption in PCT, 2% in rest of nephron
52
Q

What is the fate of glucose if an individual has plasma [glucose] > 10mM?

A
  • Exceed capacity for SGLT-2 etc for reuptake of glucose
  • Glycosuria ensues; not able to reabsorb all glucose load
  • Tm for glucose reabsorption exceeded

RED - Kidney Pharmacology & Therapeutics (5 decks)

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