L7 Renal NaCl Transport Flashcards
sodium
- proportion in body compared to other ions? to extracellular cations?
- proportion of Na in ECF? ICF? remaining 15% in?
- ___ Na transport occurs in most nephron segments
- rate of transport/cm of tubule length is highest in ______ but largest fraction of reabsorption occurs in ______ ( > ___%)
- tubule [Na] variation?
- by end of tubule, ___% of filtered load remains in the urine
- juxtamedullary nephrons reversal in potential characteristics
sodium
- most abundant ion in the body, main extracellular cation
- 66% of body sodium in ECF ([Na] ~ 130-140 mM), ~ 10% in ICF (10-25 mM), rest in bone
- active Na transport occurs in most nephron segments
- rate of transport/cm of tubule length is highest in medullary ascending limb BUT largest fraction of reabsorption occurs in proximal tubule ( > 60%)
- tubule [Na] stays constant regardless of the high reabsorption because water flow follows Na
- by end of tubule, 0.4% of filtered load remains in the urine
- juxtamedullary nephrons: specialized for concentrating urine (don’t fine-tune ion balance the same way cortical nephrons do) → electrical potential along the tubule stays relatively constant → no reversal in potential (as opposed to cortical nephrons)
routes of transepithelial transport? (2)
explain how it looks like a circuit
electrical gradient across cell membrane ___ (< > ?) paracellular pathway since ______
-transcellular + paracellular (through tight junctions)
- favorable gradient for Na entry is generated by basolateral Na/K ATPase
like a circuit:
- smaller resistance through paracellular route
- battery for flow is ATPase
- electrical and chemical gradient (concentration gradient)
- electrical gradient across cell membrane»_space; paracellular pathway since the junctions are so leaky
proximal tubule apical and basolateral cotransporters and exchangers
apical:
- organic solute cotransporters (ex. glucose)
- Na⁺/H⁺ exchangers
basolateral:
- Na⁺, HCO₃⁻, CO₃²⁻ cotransporters
- 3 Na⁺/Ca²⁺ exchangers
Na⁺ transport
- usually diffusion: active or passive? trans or paracellular?
- other methods? (2)
Na⁺ transport:
- usually passively and paracellularly diffuses out of basolateral membrane
- Na⁺/H⁺ exchanger: drives transepithelial HCO₃⁻ reabsorption
- cotransporter: carries 1 CO₃²⁻ and 1 HCO₃⁻ → allows Na⁺ to be driven across basolateral membrane (by negative membrane potential)
Ca²⁺ transport characteristics
Ca²⁺ transport:
- intracellular calcium is kept very low (important secondary messenger)
- gets transported out in exchange for sodium (3 Na⁺ in : 1 Ca²⁺ out) - !! Na⁺ should go out → gets recycled by Na⁺/K⁺ pump to basolateral side
- intracellular Ca²⁺ activity regulates rate @ which sodium enters the cell
- ↓ Na⁺/K⁺ pump activity → intracellular Na⁺ ↑ → Ca²⁺ ↑
explain Regulatory Volume Decrease
Regulatory Volume Decrease
hypotonic medium → cells swell → Ca²⁺ channels activate → transient Ca²⁺ ↑ → Ca²⁺ activates K⁺ and Cl⁻ channels → ions exit and water follows → cell shrinks (RVD)
- blocking Ca²⁺ channels or lowering extracellular Ca²⁺ prevents RVD
NHE3
- ___ NHE subfamilies, ___ isoforms in total
- renal ___ ___ has NHE3 isoform
- exchanges 1 Na⁺ : 1 H⁺ on apical membrane (electroneutral)
- example of ___ ___ transport
- deleting carboxy terminal half → ______
- Km (Michaelis constant) for Na⁺ ≈ ___mM + explain what it means
- has ___ transport + ___ sites (when ___ exceeds some value in the cell, the turnover of the transporter gets triggered)
inhibited by:
- ___ and ___ ___
- ___ ___ (inhibit ___ reabsorption)
NHE3
- 3 NHE subfamilies, 13 isoforms in total
- renal brush border has NHE3 isoform
- exchanges 1 Na⁺ : 1 H⁺ on apical membrane (electroneutral)
- secondary active transport
- deleting carboxy terminal half → reduces activity
- Km (Michaelis constant) for Na⁺ ≈ 10mM (NHE transporter is at 50% capacity when intracellular [Na⁺] ≈ 10 mM)
- has H⁺ transport + modifier sites (when pH exceeds some value in the cell, the turnover of the transporter gets triggered)
inhibited by:
- PKA and PKC phosphorylation
- amiloride analogs (inhibit Na⁺ reabsorption)
thin limbs of loop of henle most developed in ______ nephrons
thin limbs of loop of henle most developed in juxtamedullary nephrons
Thin Descending Limb Of Loop Of Henle
- little ___ transport due to ______
- ___ water permeability allows fluid reabsorption due to elevated ___ ___ of interstitium
- ___ and ___ both diffuse into lumen
Thin Descending Limb
- little active transport due to low Na+/K+ ATPase activity
- high water permeability allows fluid reabsorption due to elevated osmotic pressure of interstitium
- NaCl and urea both diffuse into lumen
Thin Ascending Limb Of Loop Of Henle
- little ___ transport due to ______
- ___ water permeability, but NaCl is ___ reabsorbed to achieve ______
Thin Ascending Limb
- little active transport due to low Na+/K+ ATPase activity
- low water permeability, but NaCl is passively reabsorbed to achieve osmotic equilibration
Thick Ascending Limb Of Loop Of Henle
- function? [NaCl] = ___ mM by the end (___ than plasma)
- reabsorbs salt at ___ rates but is ___ (impermeable or permeable) to water
- some apical ___ exchangers → HCO₃⁻ bicarbonate reabsorption
- ___ at ___ membrane cotransports ___, ___, ___ (all at once from the tubular lumen to epithelial cells - electroneutral) → ___ is recycled on apical side of TAL (brought back to the lumen); otherwise it would run out in cells since there’s»_space; Na⁺
=> lumen in TAL is ___ (positive or negative) compared to the interstitium (due to ______) → drives ______ (Mg²⁺ - paracellular) - NKCC2 sensitive to ___ ___ (e.g.: furosemide, bumetanide) - bind to ___-binding site on transporter → prevent ___ reabsorption
- relatively ___ electrical resistance (___-fold higher than proximal tubule)
- main site of energy input for ___ ___ ___
- electrical resistances ___ from proximal tubule to distal nephron (becomes less ___) → helps maintain the gradients generated by transport
Thick Ascending Limb Of Loop Of Henle
- diluting segment: [NaCl] = 30 mM by the end (lower than plasma)
- reabsorbs salt at high rates but is impermeable to water
- some apical Na⁺/H⁺ exchangers → HCO₃⁻ bicarbonate reabsorption
- NKCC2 at apical membrane cotransports 1Na⁺, 1K⁺, 2Cl⁻ (all at once from the tubular lumen to epithelial cells - electroneutral) → K⁺ is recycled on apical side of TAL (brought back to the lumen); otherwise it would run out in cells since there’s»_space; Na⁺
=> lumen in TAL is positive compared to the interstitium (due to Cl⁻ reabsorption overall > than other ions and K⁺ recycling) → drives passive reabsorption of divalents (Mg²⁺ -paracellular) - NKCC2 sensitive to loop diuretics (e.g.: furosemide, bumetanide) - bind to chloride-binding site on transporter → prevent Na⁺ reabsorption
- relatively low electrical resistance - ions move freely (2-fold higher than proximal tubule)
- main site of energy input for counter current multiplier
- electrical resistances decreases from proximal tubule to distal nephron (becomes less leaky) → helps maintain the gradients generated by transport
Na⁺/K⁺ ATPase
- in ___ membrane of renal tubule
- drives ___ transport by generating ___
- 1 ATP hydrolyzed to transport ___ out and ___ in
- has ___ intermediate
- functional heterotrimer (ɑ, β, ɣ subunits), multiple isoforms
- ɑ subunit: ___ + contains ___ binding site
- β subunit: for ___ + ___ of ______ (trafficking)
- γ subunit / FXYD subunit: modulates _______
- sensitive to cardiac ___ ___(floxglove), ___ : inhibit ___ transport → increased ___ → increased ___ ___
Na⁺/K⁺ ATPase
- in basolateral membrane of renal tubule
- drives transepithelial transport by generating ∆μNa
- 1 ATP hydrolyzed to transport 3Na⁺ out and 2K⁺ in
- has phosphorylated intermediate
- functional heterotrimer of ɑ, β, ɣ subunits, multiple isoforms
- ɑ subunit: catalytic + contains ouabain binding site
- β subunit: for assembly + export of pump to plasma membrane (trafficking)
- γ subunit / FXYD subunit: modulates pump function
- sensitive to cardiac glycosides digoxin (floxglove), ouabain : inhibit Na⁺ transport → increased Ca²⁺ → increased muscle contraction
structural domains of the Na⁺/K⁺ ATPase:
- ___ domain: ______
- ___ ___ domain : ______
- ___ domain
- ___ domain: ______
structural domains of the Na⁺/K⁺ ATPase:
- transmembrane domain where ions traverse through bilayer
- nucleotide binding domain (N) : ATP binding
- actuator (A) domain
- phosphorylation (P) domain: for conformational change
Na⁺/K⁺ ATPase conformational change
- E1: binding site faces ___ → high ___ affinity
- E2: binding site faces ___ → high ___ affinity
mechanism:
______
Na⁺/K⁺ ATPase
translocation involves conformational change from E1 to E2
- E1: binding site faces cytoplasm → high Na⁺ affinity
- E2: binding site faces ECF → high K⁺ affinity
mechanism:
E1 conformation → 3Na⁺ bind → cleavage of ATP → phosphate transferred onto pump → conformation change → Na⁺ ions release into ECF and K⁺ binds to pump→ phosphate cleavage from pump → K⁺ released into cell
distal convoluted tubule
- multiple cell types → smooth transition from ___ ___ to ___ ___
- ___ water permeability
- Vₜ (transepithelial voltage) becomes increasingly ___ (vs ___ Vₜ in TAL)
- transporters for ___ on ___ side
thiazide sensitive cotransporter (TSC/NCC)
- inhibited by thiazide
- doesn’t carry K⁺ like NKCC2
- electroneutral
distal convoluted tubule
- multiple cell types → smooth transition from distal tubule to collecting duct
- low water permeability
- Vₜ (transepithelial voltage) becomes increasingly negative (vs positive Vₜ in TAL)
- transporters for Cl⁻ on basolateral side
thiazide sensitive cotransporter (TSC/NCC)
- inhibited by thiazide
- doesn’t carry K⁺ like NKCC2
- electroneutral
late distal tubule / cortical collecting duct
- ___ cells : ___ transport, respond to ___
- ___ cell : ______
! coupled or not to each other?
Na⁺ reabsorbed according to Koefoed-Johnson + Ussing model
- Na⁺ channel is ___
- sensitive to K⁺-sparing diuretic (___): no Na⁺ absorbed → no ___ absorbed → increased ___ of ___
luminal voltage may be:
- positive due to ___ ___
- negative due to ___ ___
→ tends to cause K⁺ to ______
→ amiloride → blocked ___ ___ → no ___ ___
- vasopressin/ADH stimulates ___ ___ → reabsorption of water during antidiuresis (prevention of excessive urine)
- triggers synthesis of ___ → activation of ___ → phosphorylate ___ to get inserted → increased permeability of ___ membrane
- Na⁺/H⁺ pump on ___ side of cell, channel for K⁺ to prevent it from building up inside the cell
late distal tubule / cortical collecting duct
- principal cells : Na⁺ transport, respond to aldosterone
- intercalated cell : acid-base regulation
! not coupled to each other by gap junctions since they have different functions
Na⁺ reabsorbed according to Koefoed-Johnson + Ussing model
- Na⁺ channel is ENaC
- sensitive to K⁺-sparing diuretic (amiloride): no Na⁺ absorbed → no water absorbed → increased excretion of water
luminal voltage may be:
- positive due to H⁺ secretion
- negative due to Na⁺ absorption
→ tends to cause K⁺ to exit into lumen
→ amiloride → blocked Na⁺ entry → no K⁺ secreted
- vasopressin/ADH stimulates water permeability → reabsorption of water during antidiuresis (prevention of excessive urine)
- triggers synthesis of cAMP → activation of PKA → phosphorylate aquaporins to get inserted → increased permeability of apical membrane
- Na⁺/H⁺ pump on basolateral side of cell, channel for K⁺ to prevent it from building up inside the cell
