L8 Renal NaCl Transport II Flashcards
Kofoed-Johnsen + Ussing Model
- what did it demonstrate using frog skin?
- what are the effects of Na⁺ and K⁺ ↑ on the luminal and basolateral side? what does it demonstrate on ion diffusion?
- frog skin generates electrical voltages and currents across its surface
- frogs have renal-like transporters on their skin that reabsorb salt from the environment - controlled
- ions can only move through the epithelial layer, not around it
luminal/ apical side:
↑ [Na⁺] → apical potential more negative relative to the basal side (blood) = Na⁺ diffuses into basal side
no significant effect with K⁺
basolateral side:
- ↑ [K⁺] → transepithelial potential more positive = K+ diffuses into basolateral membrane
short-circuit current technique
- what is done?
- what’s the magnitude of current required?
- what does it quantify?
- how are the results validated?
- current is passed across the epithelium to bring the transepithelial voltage to zero
- the magnitude of current required is proportional to the rate of Na⁺ transport across the membrane
- used to quantify sodium reabsorption
- validated using radioactive sodium tracers
patch clamp technique
- why is it used instead of the short circuit current technique?
- how does it work?
e.g. : what did it prove on ENaC?
patch clamp technique
- ↑ [Na⁺] → short circuit current shows saturation due to transporter that carries [Na⁺] through membrane
- method to electrically isolate the membrane + record ion channel activity
e.g. : used to prove that ENaC is an epithelial sodium channel
ENaC – Epithelial Na⁺ Channel
- where is it located?
- what is it highly selective for? what is it permeable to?
- low or high single-channel conductance? slow or fast gating kinetics?
- low single-channel conductance and slow gating kinetics
- Kₘ for Na⁺ ~ ___ mM – shows saturation
- blocked by ___?
- composed of ___ homologous subunits: ______, each with ___ transmembrane segments
- mutations in β or γ subunits → Liddle syndrome: rare form of hereditary ___ due to ___ ___
ENaC – Epithelial Na⁺ Channel
- on apical membrane of principal cells in the cortical collecting duct (CCD)
- highly selective for Na⁺ over K⁺ but also permeable to H⁺ and Li⁺ (used in psychiatric treatment but can damage CCD cells if absorbed excessively)
- low single-channel conductance and slow gating kinetics
- Kₘ for Na⁺ ~ 5 mM – shows saturation
- blocked by amiloride (clinical diuretic)
- composed of 3 homologous subunits: α, β, and γ, each with 2 transmembrane segments
- mutations in β or γ subunits → Liddle syndrome: rare form of hereditary hypertension due to Na⁺ hyperabsorption
medullary collecting duct
outer stripe:
- lumen-___ (+ -?) potential due to ______
inner stripe:
- intercalated cells present?
- ___ reabsorption → lumen-___ (+ -?) potential
- uses a ______ Na⁺ channel (ENaC or no?), which is inhibited by ___
- Na⁺ reabsorption mechanism?
medullary collecting duct
outer stripe:
- lumen-positive potential due to H⁺ secretion by intercalated cells
inner stripe:
- no intercalated cells present
- Na⁺ reabsorption → lumen-negative potential
- uses a non-selective Na⁺ channel (distinct from ENaC), which is inhibited by cGMP
- Na⁺ reabsorption mechanism: high blood volume → release of ANP → inhibits Na⁺ reabsorption by acting via cGMP + increases GFR → corrects hypertension by ↑ Na⁺ (and water) excretion
Na⁺ transport summary
Early Proximal Tubule
Thick Ascending Limb (TAL)
Distal Convoluted Tubule (DCT)
Cortical Collecting Duct (CCD)
Na⁺ transport summary
Early Proximal Tubule
- Na⁺ reabsorbed with organic solutes
- Na⁺/H⁺ exchanger helps recover bicarbonate
- also allows paracellular ion flow via tight junctions
Thick Ascending Limb (TAL)
- “diluting segment”
- robust Na⁺ reabsorption via NKCC2 (Na⁺/K⁺/2Cl⁻ cotransporter)
- some Na⁺/H⁺ exchange for bicarbonate recovery
- crucial in establishing the countercurrent multiplier system
Distal Convoluted Tubule (DCT)
- uses Na⁺/Cl⁻ cotransporter (NCC)
- has low water permeability → urine dilution
Cortical Collecting Duct (CCD)
- main Na⁺ transport via ENaC
- K⁺ either effluxes due to depolarization or is recycled
NaCl balance
what happens to Na⁺ balance after an increase in Na⁺ intake?
- delayed increase in sodium excretion → return to sodium balance, but at a higher baseline (as much Na⁺ excreted than took in but higher total body Na⁺ because of what was retained during the delayed response)
=> same intake results in a greater total body sodium → ↑ water retention → ↑ fluid volume → ↑ body weight
how does aldosterone affect Na⁺ excretion and weight?
what is mineralocorticoid escape and why is it important? what’s the mechanism?
- administering aldosterone → stimulates CCD to reabsorb more Na⁺ and water → rapid drop in Na⁺ excretion → fluid retention and weight gain
- compensatory mechanism that prevents continuous Na⁺ and water retention despite high aldosterone levels
- without it: chronic aldosterone stimulation → severe hypertension
mechanism:
- ↑ ECF volume → ↑ hydrostatic pressure in peritubular capillaries around the proximal tubule → inhibits Na⁺ reabsorption at the PCT → even with increased GFR, Na⁺ is lost in the urine
- in inner medullary collecting duct: ↑ blood volume → release of ANP → inhibits Na⁺ reabsorption by acting via cGMP + increases GFR → ↑ Na⁺ and water excretion
Gedanken experiment
- intracellular and extracellular compartments have equal osmolalities
- ___ major intracellular ion
- ___ major extracellular ion
infuse 1.5 L of water (hypotonic) into the ECF → ?
infuse 1.5 L of isotonic saline into the ECF → ?
add only salt to the ECF → ?
which is most efficient for ECF volume increase?
Gedanken experiment
- intracellular and extracellular compartments have equal osmolalities
- K⁺ major intracellular ion
- Na⁺ major extracellular ion
infuse 1.5 L of water (hypotonic) into the ECF → ?
- dilutes ECF osmolality
- ↓ [Na⁺] in plasma
- some water shifts into the ICF to equilibrate
- slight increase in total ECF volume
infuse 1.5 L of isotonic saline into the ECF → ?
- no osmotic gradient → no water shift into cells → all 1.5 L remains in the ECF → expands ECF
add only salt to the ECF → ?
- raises ECF osmolality
- water shifts from ICF → ECF
- expands ECF without adding any water
what is the relationship between Na⁺ excretion and circulating volume?
- circulating volume is the main determinant of Na⁺ excretion
- Na⁺ excretion is the main determinant of circulating volume
=> tight regulatory feedback loop
↓ circulating volume response mechanism?
detected by pressure receptors in vasculature, renal baroreceptors, cardiac atria sensors (central pressure receptors)
response:
↑ AVP/ADH → retains water →↓ ANP → reduces natriuresis ([Na⁺] in urine) → ↑ Renin → ↑ Angiotensin II → ↑ Aldosterone → promotes Na⁺ reabsorption → ↓ Na⁺ excretion
what happens to sodium excretion when a person is immersed in warm water?
immersion causes hydrostatic pressure to push fluid from legs into the central circulation → central volume expansion triggers baroreceptors in the cardiac atria and great vessels → simulates volume overload → causes increased Na⁺ excretion
