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Flashcards in 6 Sodium Homeostasis Deck (21)
1

Sodium homeostasis

  • Na
  • Intracellular Na
  • Extracellular Na
  • Effect of Na on extracellular fluid volume (ECFV)

  • Na
    • Major extracellular cation
    • Main solutes in the extracellular space (along w/ anions)
  • Intracellular Na
    • Maintained at low levels (10-20 mM) by Na/K ATPase which transports Na out of cells
  • Extracellular Na
    • Maintained at high levels (140 mM)
    • Major determinnat of extracellular fluid volume (ECFV)
  • Effect of Na on extracellular fluid volume (ECFV)
    • Increase Na content --> increase ECFV
    • Decrease Na content --> decrease ECFV

2

Changes in ECFV

  • Na excretion regulation
  • Hormones that regulate ECFV by altering Na excretion
    • Factors that enhance Na reabsorption
    • Factors that inhibit Na reabsorption

  • Na excretion regulation
    • Kidney regulates urinary Na excretion
    • Na[in] = Na[out] to prevent changes in ECFV
    • Rates of Na excretion vary w/ Na intake
      • ► no normal values for rates of Na excretion
  • Hormones that regulate ECFV by altering Na excretion
    • Factors that enhance Na reabsorption
      • AII
      • Arginine vasopressin (AVP)
      • Aldosterone
    • Factors that inhibit Na reabsorption: natriuretic factors
      • Atrial natriuretic peptide
      • Dopamine
      • Endothelin
      • Ouabain & ouabain analogues

3

Steady state conditions: Na[in] vs. Na[out]

  • Normally
  • Abruptly increase Na[in] & maintain it at a high level
  • Abruptly decrease Na[in] & maintain it at a low level
  • How to estimate Na[in]

  • Normally
    • Na[in] = Na[out]
    • ECFV & weight remain constant
  • Abruptly increase Na[in] & maintain it at a high level
    • Delay (days) until rate of Na[out] increases to match Na[in]
    • Positive Na balance (Na retention): increase ECFV, weight, & Na[out]
    • Increase Na --> retain salt & water --> expand volume --> kidney excretes Na --> valence --> weight stabilizes
  • Abruptly decrease Na[in] & maintain it at a low level
    • Delay (days) until rate of Na[out] decreases to match Na[in]
    • Negative Na balance: decrease ECFV, weight, & Na[out]
    • Decrease Na --> excrete salt & water --> reduce volume --> kidney retains Na --> valence --> weight stabilizes
  • How to estimate Na[in]
    • Collect urine for 24 hours
    • Measure how much Na is in urine (Na[in] = Na[out])

4

Tubular reabsorption of Na

  • Glomerulus
  • Proximal tubule
  • LOH
  • Distal convoluted tubule
  • Collecting duct
  • Earlier vs. later segments of the nephron

  • Glomerulus
    • Filters 1 lb of Na / day
  • Proximal tubule
    • 65%
  • LOH
    • 25-30%
  • Distal convoluted tubule
    • 3-5%
  • Collecting duct
    • 1-3%
  • Earlier vs. later segments of the nephron
    • Most Na reabsorption occurs in earlier segments
    • Most fine-tuning of Na reabsorption occurs in later segments

5

Mechanisms of Na excretio

  • Mechs by which kidney can alter Na excretion
  • Total Na excretion
  • Na filtration in the glomerulus

  • Mechs by which kidney can alter Na excretion
    • Via changes in filtered load of na
    • Via changes in the fraction of filtered Na that's reabsobed
  • Total Na excretion
    • = amt filtered - amt reabsorbed
  • Na filtration in the glomerulus
    • Na is freely filtered at the glomerulus
    • Amt of Na filtered = GFR * PNa = 150 L/day * 140 mmols/L = 21,000 mmols/day = 21 moles/day = 0.5 kg (~1 lb)

6

Starling forces: GFR

  • Hydrostatic pressure gradient (ΔP)
  • Oncotic pressure gradient (Δπ)
  • Major determinant of GFR
  • Glomerular capillary flow rate

  • Hydrostatic pressure gradient (ΔP)
    • Major force driving filtration across the glomerular capillary
    • Tends to be stable throughout the capillary
  • Oncotic pressure gradient (Δπ)
    • Major force retaining fluid within the glomerular capillary
      • Exerted by proteins
    • Not stable throughout the capillary
      • Filtration --> protein concentration increases --> oncotic pressure increases
  • Major determinant of GFR
    • Difference b/n hydrostatic & oncotic pressure over the glomerular capillary
    • Increase hydrostatic pressure --> increase filtration
    • Increase oncotic pressure --> decrease filtration
  • Glomerular capillary flow rate
    • Determinant of GFR
    • Influences the rate of rise of oncotic pressure during filtration
    • Rapid flow rate --> slower rise in oncotic pressure
    • Slower flow rate (ex. when AII constricts EffA) --> faster rise in oncotic pressure

7

Tubular reabsorption of filtered Na

  • Fate of selected filtered solutes
  • Polarity of tubular epithelial cells

  • Selected filtered solutes
    • Removed from the ultrafiltrate by epithelial cells that line the nephron
      • Some solutes (ex. Na) pass through the cells by crossing the apical & basolateral plasma membranes
      • Some solutes pass b/n cells via a paracellular pathway
    • Enter the interstitium
    • Taken up by blood vessels
  • Tubular epithelial cells exhibit polarity
    • Dif transporters are located on the apical & basolateral sides of the membrane
    • Allows epithelial cells to transport solutes in a vectorial/directional manner
    • Achieved by chemical & electrical gradients

8

Proximal tubule (PT)

  • Na reabsorption
  • Transporters that allow Na to enter the cell across the apical plasma membrane
  • Transporters that allow Na to exit the cell across the basolateral plasma membrane into the interstitial space

  • Na reabsorption
    • 65% of filtered Na is reabsorbed
    • Na croses the apical membrane transcellularly via co-transporters/exchangers
    • Na absorption is iso-osmotic
    • Na/K ATPase: driving force for Na reabsorption
    • Some Na transport occurs w/ Cl via the paracellular pathway in the late PT
  • Transporters that allow Na to enter the cell across the apical plasma membrane
    • Na/H exchanger
    • Na/glucose co-transporter
    • Na/amino acid co-transporters
    • Na/PO4 co-transporter
  • Transporters that allow Na to exit the cell across the basolateral plasma membrane into the interstitial space
    • Na/K ATPase
    • Na/HCO3 co-transporter

9

Proximal tubule (PT)

  • Basolateral Na/HCO3 transporter
  • Anion reabsorption
  • Cl transport

  • Basolateral Na/HCO3 transporter
    • Na/K ATPase --> negative potential inside the cell
    • 3 HCO3 out, 1 Na in
    • 90% of filtered HCO3 is reabsorbed in the PT
  • Anion reabsorption
    • Anions are reabsorbed w/ cations to maintain electroneutrality
  • Cl transport
    • Paracellular pathway: some Cl is reabsorbed across tight junctions in the latter par to fhte PT
    • Transcellular pathway: Cl transport occurs across the apical membrane via anion exchangers
      • Cl/formate exchanger
      • Cl/HCO3 exchanger
      • Cl/oxalate exchanger

10

Proximal tubule (PT)

  • Early vs. late paracellular Na transport
  • Fate of Na once it reaches interstitial space
  • Rate limitng step for Na reabsorption in the PT
  • Main factors regulating fluid & Na uptake in the peritubular capillary

  • Early vs. late paracellular Na transport
    • Early: Na reabsorbed w/ HCO3
    • Late: Cl conc in tubular lumen > interstitial space --> Cl moves across tight junctions --> (+) lumen potential --> drives Na through tight junction
  • Fate of Na once it reaches interstitial space
    • Enter pertibular capillaries
    • Leak back across tight junctions into tubular lumen
  • Rate limitng step for Na reabsorption in the PT
    • Uptake of Na into peritubular capillaries by solvent drag (Starling forces)
  • Main factors regulating fluid & Na uptake in the peritubular capillary
    • Oncotic & hydrostatic pressures
    • Increase oncotic or decrease hydrostatic pressure --> increase Na & water reabsorption
    • Decrease oncotic or increase hydrostatic pressure --> decrease Na & water reabsorption

11

Na/K ATPase

  • General
  • Driving force for other solute transport
  • Driving force for Na uptake across the apical membrane is used to...
  • Side benefit
  • Mitochondria

  • General
    • Workhorse of the cell
    • Pumps 3 Na out for 2 K in
      • --> low intracellular Na (chemical gradient)
      • --> (-) intracellular charge (electrical gradient)
  • Driving force for other solute transport
    • Movement of Na across the PT
  • Driving force for Na uptake across the apical membrane is used to...
    • Reabsorb filtered glucose, aminoa cids, & phosphate in the PT
  • Side benefit
    • Translocation of Na & other solutes across the membrane --> osmotic driving force for water reabsorption
  • Mitochondria
    • Large number in PT b/c a lot of ATP is required

12

Loop of henle (LOH)

  • Na reabsorption
  • Active vs. passive Na transport

  • Na reabsorption
    • 25-35% of filtered Na reabsorption occurs here
    • 50% of reabsorbed na travels through the transcellular pathway & 50% through the paracellular pathway
    • Na crosses the apical membrane via the Na/K/2Cl co-transporter
    • Loop diuretics block Na reabsorption in this segment by blocking the Na/K/2Cl transporter
    • Paracellular transport of Ca & Mg occur here
  • Active vs. passive Na transport
    • No active Na transport across the TnDL & TnAL
      • Some passive Na reabsorption occurs across the TnAL
    • Na is actively absorbed across the TkAL
      • 25-30% of the filtered Na is reabsorbed here

13

Loop of henle (LOH)

  • Na/K/2Cl co-transporter
  • Transcellular vs. paracellular pathway in the TkAL
  • ROMK (renal outer medullar K channel)
  • Na/K ATPase
  • Cl channel

  • Na/K/2Cl co-transporter
    • Na: urine --> apical membrane --> TkAL
    • Inhibited by loop diuretics (ex. furosemide, bumetanide, torsemide)
  • Transcellular vs. paracellular pathway in the TkAL
    • 50% transcellular (through cells)
    • 50% paracellular (b/n adjacent cells)
      • Depends on positive charge build-up in the TkAL
  • ROMK (renal outer medullar K channel)
    • K: TkAL --> apical plasma membrane --> tubule lumen (urine)
    • Creates (+) in the tubule lumen / urine
    • (+) charge drives Na, Mg, & Ca: tubular lumen (urine) --> capillary lumen (blood) paracellularly
      • Passive process so no energy cost
    • Maximizes Na uptake & ATp fuel efficiency
  • Na/K ATPase
    • 3Na: TkAL --> basolateral membrane --> interstitial space (blood)
    • 2K: capillary lumen (blood) --> basolateral membrane --> TkAL
  • Cl channel
    • Cl: TkAl --> basolateral membrane --> capillary lumen (blood)

14

Distal nephron

  • Na reabsorption
  • Apical membrane (early)
  • Apical membrane principal cells (late)
  • Basolateral membrane
  • Epithelium

  • Na reabsorption
    • 4-8% of filtered Na is reabsorbed here (final site)
  • Apical membrane (early)
    • Na/Cl co-transporter
      • 1 Na & 1 Cl: tubular lumen (urine) --> distal convoluted tubule
      • Acitvated by aldosterone
      • Inhibted by thiazide diuretics (used to treat HTN)
    • Transcellular transport of Ca & Mg
      • 1 Ca & 1 Mg: tubular lumen (urine) --> distal convoluted tubule
      • Inhibit Na/Cl co-transporter (ex. w/ thiazides) --> increase Ca/Mg transport
  • Apical membrane principal cells (late): ENaC (epithelial Na channel)
    • Na: tubular lumen (urine) --> intracellular
    • Actiaved by aldosterone & arginine vasopressin
    • Inhibited by K sparing diruetics (amiloride & traimterene), trimethoprim, & by aldosterone antagonists (spironolactone, eplerenone)
  • Basolateral membrane: Na/K ATPase
    • 3 Na: intracellular space --> interstitium (blood)
    • 2 K: interstitium (blood) --> intracellular space
  • Epithelium
    • High resistance --> minimal back leak of Na paracellularly

15

Other Na transporters: intercalated cells

  • Acid-base transporting cells in the latter distal nephron
  • Reabsorption of filtered Na via an apical Na-dependent Cl/HCO3 exchanger
    • Operates in parallel in another apical Cl/HCO3 exchanger (pedrin)
  • Little Na/K ATPase so unclear how Na leaves the cell

16

Renin

  • Secreted by...
  • Secretion stimulated by...
  • Release is regulated by...
  •  

  • Secreted by...
    • JG cells
  • Secretion stimulated by...
    • Decreased ECFV
    • Perceived decreased effective arterial volume (ex. CHF & cirrhosis)
  • Release is regulated by...
    • Amt of solute delivered to the macula densa
      • Function of solute reabsorption in the proximal nephron
    • Stretch of the AffA
      • Function of the plasma volume
    • SNS
    • Prostaglandins (PGE)

17

Angiotensin II

  • Renin
  • ACE
  • AII (low conc) vs. GFR
  • AII (high conc) vs. GFR
  • AII vs. systemic BP: AII increases systemic BP via...

  • Renin
    • Cleaves angiotensinogen --> angiotensin I
  • ACE
    • Converts angiotensin I --> angiotensin II
  • AII
    • Stimulates secretion of aldosterone by the adrenal cortex
    • Potent systemic vasoconstrictor
  • AII (low conc) vs. GFR
    • Constricts EffA --> reduces RPF (& GPF) --> increases glomerular hydrostatic pressure --> increases FF while maintaining GFR
    • Increase in glomerular capillary pressure is countered by increased glomerular capillary oncotic pressure
      • Opposing effects --> net effect: maintain GFR
    • Increase peritubular oncotic pressure + decrease peritubular hydrostatic pressure --> increase Na (& water) reabsorption in the proximal nephron
  • AII (high conc) vs. GFR
    • Constricts both EffA & AffA
  • AII vs. systemic BP: AII increases systemic BP via...
    • Arterial vasoconstriction
    • Increased proximal tubular Na reabsorption
    • Released aldosterone --> increased distal tubular na reabsorption

18

AII vs. GFR

  • Effects of EffA constriction on GFR
  • Effects are dependent on...
  • Effect of EffA constriciton on FF
  • Effect of AII on Na/H exchanger

  • Effects of EffA constriction on GFR
    • Increase hydrostatic pressure --> increase GFR
    • Decrease renal plasma flow --> increase oncotic pressure --> decrease GFR
    • Net result: maintain GFR
  • Effects are dependent on...
    • Changes in systemic BP
    • Local effects on renal blood flow
  • Effect of EffA constriciton on FF
    • FF = GFR / RPF
    • AII --> unchanged GFR + decreased RPF --> increased FF
    • --> increased oncotic pressure (protein conc) + decreased hydrostatic pressure
    • --> increased Na & water reabsorption
  • Effect of AII on Na/H exchanger
    • AII --> increase Na/H in PT --> increase Na reabsorption

19

Arginine vasopressin

  • Secreted in response to...
  • Effect on Na handling

  • Secreted in response to...
    • Osmotic stimuli
    • Non-osmotic stimuli (ex. volume depletion, reduced "effective" arteriolar volume)
  • Effect on Na handling
    • Activates the Na/K/2Cl co-transporter in the TkAL
      • Increases Na transport across the cells lining the TkAL
    • Acitaves NCC & ENaCs in the distal nephron

20

Aldosterone

  • Secreted from...
  • Secreted i.r.t. ...
  • Effect
  • Channels activated in the distal convoluted tubule
  • Channels activated in the convoluted tubule
  • Mechs by which aldosterone regulates ENaCs

  • Secreted from...
    • Adrenal cortex
  • Secreted i.r.t. ...
    • AII
    • Increased plasma K
  • Effect
    • Increases Na reabsorption in the distal nephron
    • Increases K & H secretion in the distal nephron
  • Channels activated in the distal convoluted tubule
    • Na/Cl co-transporter (thiazide-sensitive)
    • Na/K ATPase
  • Channels activated in the convoluted tubule
    • ENaC channel (amiloride-sensitive)
    • Na/K ATPase
  • Mechs by which aldosterone regulates ENaCs
    • Exerts effects on ENaC mRNA in the kidney --> increases expression of the alpha subunit
    • Regulates ENaC via post-translational mechs
      • Redistributing channels from an intracellular pool to the apical plasma membrane
      • Increasing open probability of channels at the apical plasma membrane

21

Other factors that regulate renal Na excretion

  • Atrial natriuretic peptide (ANP)
  • Ouabain analog
  • Dopamine
  • Endothelin
  • Prostaglandins
  • SNS

  • Atrial natriuretic peptide (ANP)
    • Small peptide synth'd & secreted by atrial myocytes i.r.t. stretch
    • Inhibits Na/K ATPase in the inner medullary collecting tubule
      • --> increases GFR & inhibits Na reabsorption
      • --> increases urinary Na excretion
    • Inhibits ENAC
  • Ouabain analog
    • Synth'd by the adrenal glands
    • Secreted by the hypothalamus
    • Inhibits Na/K ATPase
      • --> inhibits renal Na reabsorption
      • --> increases renal Na excretion
  • Dopamine
    • Inhibits Na/H exchagner & Na/K ATPase in the PT
      • --> increases urinary Na excretion
    • Inhibits Na reabsorption in the distal nephron
  • Endothelin
    • Inhibits ENAC --> increases urinary Na excretion
  • Prostaglandins
    • Prostacyclin & PGE2 enhance renin secretoin by the JG apparatus
    • Specific prostaglandins affect glomerular hemodynamics by dilating the AffA & EffA
    • Renal prostaglandins (PGE2) inhibit Na reabsorption in the TkAL & cortical CD --> promote urinary Na excretion
  • SNS
    • Enhances renin secretion --> increase AII generation --> increase aldo secretion
    • Alpha-adrenergic receptors directly enhance renal Na reabsorption in the PT