lecture-5 regulation of tubular...
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Lecture-5
Regulation of Tubular Reabsorption
• Glomerulotubular Balance
• Peritubular Physical Forces
• Hormones
- aldosterone
- angiotensin II
- antidiuretic hormone (ADH)
- natriuretic hormones (ANF)
- parathyroid hormone
• Sympathetic Nervous System
• Arterial Pressure (pressure natriuresis)
• Osmotic factors
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Glomerulotubular Balance
Tubular
Reabsorption
Tubular Load
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Importance of Glomerulotubular Balance in Minimizing Changes in Urine Volume
GFR Reabsorption Urine Volume % Reabsorption
“perfect” glomerulotubular balance
150 148.8 1.2 99.2
no glomerulotubular balance
125 124 1.0 99.2
150 124 26.0 82.7
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Peritubular capillary reabsorption
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Peritubular Capillary Reabsorption
Reabs = Net Reabs Pressure (NRP) x Kf
= (10 mmHg) x (12.4 ml/min/mmHg)
Reabs = 124 ml/min
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Determinants of Peritubular
Capillary Reabsorption
Kf Reabsorption
Pc Reabsorption
c Reabsorption
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Determinants of Peritubular
Capillary Hydrostatic Pressure
Peritubular
Capillary (Pc)
Glomerular
CapillaryRa Re
Arterial
Pressure
Arterial Pressure Pc Reabs.
Ra Pc Reabs.
Re Pc Reabs.
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Factors That Can Influence
Peritubular Capillary Reabsorption
Kf Reabsorption
Pc Reabsorption
Ra Pc ( Reabs)
Re Pc (Reabs)
Art. Press Pc ( Reabs)
c Reabsorption
a c
Filt. Fract. c
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Effect of increased
hydrostatic pressure
or decreased colloid
osmotic pressure
in peritubular
capillaries to reduce
reabsorption
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Which of the following changes would tend to
increase peritubular reabsorption ?
1. increased arterial pressure
2. decreased afferent arteriolar resistance
3. increased efferent arteriolar resistance
4. decreased peritubular capillary Kf
5. decreased filtration fraction
Question
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Aldosterone actions on late distal, cortical
and medullary collecting tubules
• Increases Na+ reabsorption - principal cells
• Increases K+ secretion - principal cells
• Increases H+ secretion - intercalated cells
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Late Distal, Cortical and Medullary Collecting Tubules
Tubular LumenPrincipal Cells
Cl -
H20 (+ ADH)
Aldosterone
K+
Na +
ATPK+ ATP
Na +
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• Excess aldosterone (Primary aldosteronism
Conn’s syndrome) - Na+ retention,
hypokalemia, alkalosis, hypertension
Abnormal Aldosterone Production
• Aldosterone deficiency - Addison’s disease
Na+ wasting, hyperkalemia, hypotension
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Control of Aldosterone Secretion
Factors that increase aldosterone secretion
• Angiotensin II
• Increased K+
• adrenocorticotrophic hormone (ACTH)
(permissive role)
Factors that decrease aldosterone secretion
• Atrial natriuretic factor (ANF)
• Increased Na+ concentration (osmolality)
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Angiotensin II Increases Na+ and Water
Reabsorption
• Stimulates aldosterone secretion
• Directly increases Na+ reabsorption (proximal, loop,
distal, collecting tubules)
• Constricts efferent arterioles
- decreases peritubular capillar hydrostatic pressure
- increases filtration fraction, which increases
peritubular colloid osmotic pressure
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Angiotensin II increases renal
tubular sodium reabsorption
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Effect of Angiotensin II on Peritubular Capillary Dynamics
Peritubular
Capillary
Glomerular
CapillaryRa Re
Arterial
Pressure
Ang II Re Pc (peritubular cap. press.)
renal blood flow FF
c
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Ang II constriction of efferent arterioles causes Na+ and
water retention and maintains excretion of waste
productsNa+ depletion
Resistance efferent arterioles
Ang II
Glom. cap. press
Prevents decrease
in GFR and
retention of
waste products
Renal blood flow Peritub. Cap. Press.
Filt. Fraction
Na+ and H2O Reabs.
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Angiotensin II blockade decreases Na+
reabsorption and blood pressure
• ACE inhibitors (captopril, benazipril, ramipril)
• Ang II antagonists (losartan, candesartin, irbesartan)
• Renin inhibitors (aliskirin)
• decrease aldosterone
• directly inhibit Na+ reabsorption
• decrease efferent arteriolar resistance
Natriuresis and Diuresis + Blood Pressure
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Segmental Variation in the Tubular System
• The ratio of a substance’s concentration in the tubular fluid to its levels in the plasma changes along the course of the tubular system depending on how it is handled.
• The next Figure describes these changes. Notice how levels of glucose and amino acids drop to extinction even before the tubular fluid completes its passage through the proximal tubule.
• The TF/P for sodium remains 1 in the proximal tubule since Na+ and water are reabsorbed in the same proportion.
• For inulin, however, TF/P reaches 3 in the proximal tubule since 65% of water and none of the inulin is reabsorbed.
• Regarding PAH, its levels in the proximal tubule are higher than those of the others. The reason is that it is not only filtered, but also actively secreted and not reabsorbed.
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Segmental Variation in the Tubular System
• The ratio of a substance’s concentration in the tubular fluid to its levels in the plasma changes along the course of the tubular system depending on how it is handled.
• The next Figure describes these changes. Notice how levels of glucose and amino acids drop to extinction even before the tubular fluid completes its passage through the proximal tubule.
• The TF/P for sodium remains 1 in the proximal tubule since Na+ and water are reabsorbed in the same proportion.
• For inulin, however, TF/P reaches 3 in the proximal tubule since 65% of water and none of the inulin is reabsorbed.
• Regarding PAH, its levels in the proximal tubule are higher than those of the others. The reason is that it is not only filtered, but also actively secreted and not reabsorbed.
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Sodium Homeostasis• 65% is in ECF 140 mEq/L.
• 5-10% is in ICF 10-30 mEq/L.
• 25% is in bone nonexchangable.
• Na in ECF volume contraction.
• Na in ECF volume expansion and edema.
• - Most of the primary active transport in the entire tubular system is to transport Na+
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Sodium Homeostasis• Sodium is an electrolyte are major importance in the
human body. It is necessary for :1. normal extracellular volume dynamics: more Na means
volume 2. excitability of certain tissues 3. cotransport and countertransport4. countercurrent mechanism: the ability of kidney to
make concentrated urine5. Sodium accounts for a significant portion of plasma
osmolarity. The latter can be estimated by multiplying plasma sodium concentration times 2.1.
6. blood pressure
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Effect of increasing sodium intake 10-fold on urinary sodium excretion and extracellular fluid
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Sodium Balance
• Sodium balance is achieved when intake and output equal each other.
• Sodium intake is about 155mmol/d in the average American diet. Logically, the daily output would be 155mmol/d as well.
• The kidney accounts for 150mmol of this output. Hence, the kidney is a major organ in sodium homeostasis.
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Na+ & H2O reabsorption occurs as the following :
Segment Na+% H2O%
Proximal tubule 65% 65%
Descending (Henle) - 15%
Ascending (Henle 25% -
Distal tubule 5% 10%
Collecting duct 4% 9%
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• There are 2 ways to handle Na+ in the kidney
1) Though altering Glomerular Filtration or
2) Reabsorption
• Ex: when Na+ intake↑↑Na filtered ↑reabsorption
• This is called " glomerulotubular balance " to ensure that a constant fraction is reabsorbed ( ≈ 2/3 ) this occurs in the proximal tubules .
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A-Reabsorption in proximal tubules
• There are 2 ways for Na transport through the cells:1. transcellular channels ( T-max)2. paracellular tight junction
• In the early proximal tubules, tight junctions are not that tight paracellular route ( + transcellular route ) , so transport is NOT T-max dependant it is gradient-time dependant .
• Conc time in prox. tubules more chance to be reabsorbed.
• In more distal parts of the nephron , the tight junctions are tighter T-max dependant transport .
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A-Reabsorption in proximal tubules• In the late proximal tubule , Na+ is
reabsorbed with Cl- , because in the early prox.tub. , removal of large amounts of Na+ with glucose creates negativity inside the lumen. so to get back to normal , Cl- is reabsorbed. Na+ follows Cl- .
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Reabsorption of Water and Solutes
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Primary Active Transport of Na+
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Interstitial
Fluid
Tubular
Lumen
Tubular
Cells
Reabsorption of Water and Solutes is Coupled to
Na+ Reabsorption
3 Na +
2 K+ ATP
3Na +
2K+ATP Na +
- 3 mV0 mv
H20
Cl-
Urea
Na +
H +
glucose, amino
acidsNa +
- 70 mV
- 3 mV
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Na+ Clearence
• Sodium clearance can be calculated as follows:• UNa+ = 150mmol/d ÷ 1.5l/d = 100mmol/l • CNa+ = (UNa+ / PNa+) * V = (100 / 145) * 1 = 0.69ml/min• Notice that the value is less than 1 ml/min, which
indicates that sodium is mostly reabsorbed.• Sodium reabsorption is rather extensive. In order to
appreciate this, let’s do the math.• Amount of sodium filtered per day = 180l/d * 140mM =
25200mEq• Amount of sodium excreted by the kidney = 150mEq• Percent reabsorbed = 25050 / 25200 = 99.4%
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Transport characteristics of proximal tubule.
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Changes in concentration in proximal
tubule
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Transport characteristics of thin and thick loop of Henle.
•very permeable to H2O)
• Reabsorption of
Na+, Cl-, K+, HCO3-,
Ca++, Mg++
• Secretion of H+
• not permeable to H2O
~ 25% of filtered load
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Clinical point
1. Furesamide ( Lasix): a potent loop diuretic acts on the thick ascending limb of Henle TAL where it inhibits Na-2Cl-K ↑ Na Excretion.
Indicated in pulmonary edema & hypertension.
2. Thiazide/Chlorothiazide (moderate diuretic) acts on distal convoluted tubule DCT inhibiting Na/Cl reabsorption
• Those 2 diuretics are called [k+_ wasting diuretics]
•
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Clinical point cont.
• 1. Spironolactone (aldactone): works on principal cells by decreasing K+ secretion such diuretics are called [K+ sparing diuretics] or [aldosterone antagonists].
• 2. Osmotic diuretics , (ex: Mannitol) is a glomerular marker & has an osmotic effect i.e. it's not reabsorbed so it drives H2O with it , used in brain edema .
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Sodium chlorideand potassium
transport in thick
ascending loopof Henle
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Early Distal Tubule
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Early Distal Tubule
• Functionally similar to thick ascending loop
• Not permeable to water (called diluting segment)
• Active reabsorption of Na+, Cl-, K+, Mg++
• Contains macula densa
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Transport characteristics of medullary
collecting ducts
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Normal Renal Tubular Na+
Reabsorption
0.6 %
(150 mEq/day)
(16,614 mEq/day)
65 %
(6390 mEq/d)
(617 mEq/day)
2.4%
25,560
mEq/d
25 %
(1789 mEq/d)
5-7 %
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sodium homeostasis
• Three factors are principally involved in sodium homeostasis:
1. GFR,
2. Aldosterone,
3. Atrial natriuretic peptide.
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Control of Na+
• when Na+ intake GFR by : -
ECV
BP
peritubular π
• when ECV π peritubular capillary due to dilution Reabsorption.
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• When Na+ intake Glomerulotubularfeedback is not working for unknown reason Na Excretion.
Na intake pressure filtration & this is called (Pressure Natriuresis)