Glomerulus & Tubule

Master answer

NORMAL SODIUM

• Total Sodium (Na) = 4000 mmol (60 mmol/kg) 
• Distributed:
  1. Bone (45%)
  2. ECF (50%)
     • 1°ly found in ECF (major EC cation)
  3. ICF (5%)
     • 10-15 mmol/L maintained by
     • Na⁺/K⁺ ATPase
     • low g_Na → prevents influx of Na
• Role of Na
  1. Main determinant of ECF osmolality and tonicityNa/Cl ~ 90% ECF osmotic solute load
  2. Main determinant of ECFV
  3. Depolarisation in action potential 2° to ↑Na conductance
  4. Co-transport of substances across membranes (Eg. Glucose)
  5. Involved in Na+/K+ ATPase in cell membranes
• Total output =Total input
  • 1-1.4 mmol/kg/day
  • ~100-300 mmol/day in 70 kg adult
  • 10.5 g/day
• Sodium Control – Lost via:
  1. Kidneys (main) ~ lose 150 mmol/day
     • Filters 25000 mmol Na+/day
     • 99.5% reabsorbed
     • 65% PCT, 25% TAL of LoH, 5% EDCT, 4-5% LDCT and CD
  2. Sweat and GIT loss in faeces ~ lose 10 mmol/day (0.25 g/day each)

Sodium Reabsorption in Kidney

Overview of renal Na⁺ regulation:

• Thus, renal Na⁺ regulation depends on:
  • Degree of glomerular filtration of Na+ → GFR (minor)
    • Changes in GFR due to hyper or hypovolaemia will (indirectly) adjust sodium elimination. Increased plasma volume increases GFR, and vice versa.
  • Degree of tubular reabsorption of Na⁺ (major)
    This is the main mechanism for controlling sodium in euvolaemia.
    In terms of long term Na excretion; Na reabsorbed is more impt than GFR because:
    • (i) GFR is heavily autoregulated
    • (ii) Glomerulotubular balance blunts any major changes in Na+ excretion that would have resulted from minor changes in GFR changes that actually occurs
  • Na reabsorption through GIT/sweat/salivary glands:
    • Varies with diet and exercise
    • Mainly action of Aldosterone via Na/K ATPase

• Normal values
  • Na⁺ filtration: 140mmol/L x 180L/day = 25000mmol Na/day
  • Na⁺ excretion: 140mmol excreted
    • rest reabsorbed
    • Fractional excretion = 0.5%

Na+ regulation: Control of GFR

1. Intrinsic autoregulatory factors (tubuloglomerular feedback and myogenic mechanism)
   • MAP has minor effect on GFR over MAP range 70-175 mmHg → BUT changes
     in BP that invoke baroreceptor reflexes (BRR) can override these autoregulatory
     mechanisms → alter GFR and amount of Na+ filtered
2. Extrinsic factors: Body Na+ content (via ECFV)
   • Direct renal effects – ↓ [Na⁺] (or ↓ ECFV) → results in ↓ GFR due to a ↓ glomerular capillary P(HYDROSTATIC) and ↑ glomerular capillary P(ONCOTIC) → ↓ GFR and Na⁺ filtered
   • Indirect renal effects – ↓ [Na⁺] (or ↓ ECFV) → stimulates arterial, venous and cardiac BRR → neurohormonal response → to ↓ GFR and Na⁺ filtered via:
     • (i) ↑ SNS and RAAS activity → cause afferent and efferent arteriolar constriction and mesangial cell contraction
     • (ii) ↑ ADH → cause afferent arteriolar constriction and mesangial cell contraction
     • (iii) ↓ ANP → inhibit afferent arteriolar dilation and mesangial cell relaxation

Na+ Regulation: Control of Reabsorption

1. Glomerulotubular balance:
   • Intrinsic autoregulatory mechanism that minimises the effect of changes in GFR on Na⁺ and H₂O excretion
   • It functions on the basis that the PCT reabsorbs a constant proportion of glomerular filtrate (65% of filtered Na⁺ /H2O), rather than a constant amount
   • In effect – ↑ GFR = ↑ filtration of Na+/H2O = ↑ Na+/H2O reabsorption
   • Mechanism:
     • With ↑ GFR → large amount of plasma is filtered at the glomerulus → leads to ↑ π(ONCOTIC) of plasma in peritubular capillaries
   • This results in an ↑ gradient that –
     • (i) Favours tubular reabsorption, and
     • (ii) Counteracts the effect of ↑ GFR on fluid leaving the PCT
2. Renal interstitial hydrostatic pressure (Intrarenal physical factors)
   • ↓ ECFV (and ↓ Na⁺) results in ↓ MAP → leads to (i) ↓ P_HYDROSTATIC and (ii) ↑ π_ONCOTIC of peritubular capillaries → thus, ↑ Na⁺ (and ↑ H2O) reabsorption from tubular interstitium into peritubular capillaries
3. Hormonal Influences:
   • Renin
     • Released by ↓ Na delevery to macula densa or β1 stimulation secondary to volume underload
     • Tubular effects:
       • increased PCT Na/Cl reabsorption, increased tubular K secretion
       • Direct PCT effect
       • Aldosterone release
   • Aldosterone
     • Most important regulator of Na⁺ reabsorption
     • Alters protein translation (inducing production of tubular basolateral Na+/K+ATPase and luminal ENaC and K+channels) → causes ↑ Na+ reabsorption by DCT and Principal cells of CCD
     • Increased Na reabsorption throughout the GIT/sweat and salivary glands via Na/K ATPase
     • Increased H2O reabsorption and increased Na via solvent drag
   • Angiotensin II
     • Negative feedback on renin release
     • Increased aldosterone release
     • Decreased RBF and GFR
       • Direct renal arteriole constriction (efferent = afferent)
       • Mesangial cell contraction thus decreased Kf and GFR
     • Direct stimulation of Na⁺ reabsorption at PCT, and
     • Indirect stimulation of Na⁺ reabsorption via SNS, AII, and aldosterone
   • SNS
     • Direct stimulation of Na+ reabsorption at the PCT (α1 and β1 receptors), and
     • Indirect stimulation of Na⁺ reabsorption via RAAS
   • ADH
     • → ↑ Na⁺ reabsorption at the CCD (principal cells) → acts synergistically with aldosterone here
   • ANP
     • Inhibition of Na⁺ reabsorption (blockage of ENaC) in the CDs
     • ↓ RAAS and ↓ ADH activity
4. Other causes ↑Na reabsorb:
   • Cortisol
   • Oestrogen
   • GH
   • Thyroid hormone
   • Insulin
   • Dopamine
5. Other cause ↓Na reabsorb:
   • PGE2 inhibits NaK ATPase to reduce Na reabsorption
   • Glucagon
   • Progesterone
   • PTH
   • Renal vasoDilators:
     • PGs
     • Kinins
6. Pressure natriuresis & diuretics
   • renal compensatory mechanism that maintains long-term regulation of arterial BP by controlling the kidney’s excretory ability of Na⁺and H2O
7. Pharmacological agents:
   • Ouabain (a cardiac glycoside) inhibits NaK ATPase decreasing excretion
   • Loop Diuretics → ↑ Na loss

Gladwin / Bianca / JC 2019

Answer by Bianca, Gladwin, JC