Control Of Reabsorption & Secretion In The Nephron

Question 1

Secretion in the Proximal Tubule

Answer 1

• End products of metabolism e.g. organic acids and bases which need to be rapidly removed from the body are excreted here - catecholamines, bile salts, oxalate and urate.
• They are either secreted into the proximal tubule or filtered at the glomerulus, there is no reabsorption along the tubules which allows for rapid excretion.
• Toxins and drugs are also secreted into the proximal tubule to be excreted. This can prove challenging for maintaining a therapeutic effective drug concentration in the body. E.g. penicillin.
• Piggy-backs on promiscuous (demonstrating or implying an unselective approach; indiscriminate or casual) transporters.

Question 2

Reabsorption/Secretion in the Loop of Henle

Answer 2

• H2O reabsorbed through aquaporin 1 channels in thin descending limb (lined by simple shallow epithelial cells).
• Thin ascending limb impermeable to H2O but is permeable to Na+ and Cl- which move paracellularly.
• Thick ascending limb is impermeable to H2O and allows for reabsorption of Na+, Cl-, K+, HCO3-, Mg2+ and Ca2+ back into the blood. H+ is secreted into the Thick Ascending Limb. It is lined by epithelial cells with high metabolic activity.

Question 3

Reabsorption/Secretion of the Distal Convoluted Tubule

Answer 3

• Most transport is transcellular. Most tight junctions are now actually tight.
• Na+-Cl- Co-Transporter into epithelial cell from lumen of tubule.
• Mg2+ Channel (TRPM5) and Ca2+ Channel (TRPV5, TRPV6) on apical membrane transporting Mg2+ and Ca2+ from lumen of tubule into epithelial cell.
• Mg2+/Na+ Exchanger and Na+/Ca2+ Exchanger exchanges Mg2+ and Ca2+ into interstitium for Na+ to be brought into the epithelial cell across the basolateral membrane.

Question 4

Reabsorption/Secretion in the Connecting Tubule (CNT) and Cortical Collecting Duct (CCD)

Answer 4

• Two types of cell - Principal Cells (PREDOMINANT (70%); Na+ absorbing; K+ secreting; K+-sparing diuretics target Na+ here) and Intercalated Cells (30%; acid/base; energised by H+/K+ ATPase, K+ absorbed, H+ secreted; 3 types: A, B and non A-non B). Many hormones target principal cells as this is where the “fine tuning” of Na+ balance takes place.
• When ADH/AVP is released, water is also reabsorbed here.
• Bicarbonate is also reabsorbed here.
• Connecting Tubule (+20-180%) and Collecting Duct (-20-40%) are both very important for maintaining K+ balance.

Question 5

Reabsorption and Secretion in the Medullary Collecting Duct

Answer 5

• Final site for processing urine.
• Only permable to H2O if AVP?ADH is released.
• Reabsorbs Na+, Cl-, Urea (reabsorption of urea contributes to raising osmolality of the medullary interstitium), and Bicarbonate.
• Secretes H+ to regualte acid-base balance,

Question 6

Arginine Vasopressin (AVP)

Answer 6

• AKA Anti-Diuretic Hormone
• Released from the Posterior Pituary Gland when plasma osmolality (detected by osmoreceptors in the brain - circumventricular organs) is high/increased.
• Prevents water loss/diruresis / stimulates water reabsorption
• Very short half-life - 10-15mins
• Increases H2O permeability in all nephron segments beyond the Distal Convoluted Tubule

Question 7

Mechanism of Action of AVP

Answer 7

• Vasopressin Receptors (V2R) are located on the basolateral membrane of Collecting Duct Prinicipal Cells.
• AVP arrives in bloodstream and diffuses into the interstitum where it binds V2R.
• V2R is a G-protein Coupled Receptor (Gs), stimulates adenylyl cyclase and increases [cAMP]i.
• cAMP activates Protein Kinase A
• Protein Kinase A phosphorylates the intracellular pool of Aquaporin 2 (AQP2) channels which results in trafficking to the apical membrane and more H2O being reabsorbed into the plasma.
• Osmolality is REDUCED.

Question 8

Renin

Answer 8

• Rate-limiting enzyme
• Release of renin stimulated by decreased tension in the affent arterioles/decreased renal perfusion pressure, increased renal sympathetic nerve activity (triggered by baroreceptor reflex), and decreased delivery of NaCl to the Macula Densa.
• Converts Angiotensinogen into Angiotensin I by getting rid of the last 4 amino acids (Leu-Val-Tyr-Ser) of the Angiotensinogen chain.

Question 9

Angiotensin Converting Enzyme (ACE)

Answer 9

• Converts Angiotensin I to Angiotensin II

- Does this by getting rid of 2 amino acids on the Angiotensin I chain (His- Leu)

Question 10

Angiotensin II

Answer 10

• Acts on AT1 Receptors. AT1 Receptors can be found in Vascular Smooth Mucles Cells, the Hypothalamus, Zona Glomerulosa of the Adrenal Glands and the Renal Tubules.
• In Vascular Smooth Muscle Cells; increases vasoconstriction and total peripheral resistance.
• In the Hypothalamus; increases release of Arginine Vasopressin, reabsorption of water in kidneys and ECV.
• In Kidneys and Adrenal Glands; increases secretion of aldosterone from adrenal glands, sodium reabsorption in kidney and ECV.

Question 11

Mechanism of Action of Angiotensin II

Answer 11

• AT1 Receptors are found on both apical and basolateral membranes of the proximal tubule epithelia.
• Angiotensin II is released into the bloodstream and can diffuse into the blooodstream where it binds basolateral AT1 receptors. Locally produced “intra-renal” Angiotensin II binds the apical receptors.
• Mechanism still unclear but it is known that Angiotensin II stinulates activity of the Na+-H+ exchanger (NHE3) on the apical surface.
• Stimulates reabsorption of Na+ via transcellular route.

Question 12

Aldosterone

Answer 12

• Steroid Hormone
• Released from Zona Glomerulosa of the adrenal glands.
• Release stimulated by increase in K+ plasma concentration and drop in effective circulating volume (ECV; which triggers the Renin-Angiotensin-Aldosterone System)

Question 13

Mechanism of Action of Aldosterone

Answer 13

• Principal cells of the Collecting Duct contain steroid receptors (MR (mineralocoticoid receptor) and GR (glucocorticoid receptor)) and the enzyme 11betaHSD2.
• Steroid hormones appear in circulation (cortisol>aldosterone)
• Cortisol can diffuse into the cell, but is converted to inactive 11betaHSD2, which grants aldosterone specifity.
• Aldosterone diffuses into the cell and binds mineralocorticoid receptor (MR).
• MR translocates to the nucleus and promotes transcription, these transcriptions are made into protein which interact with Epithelial Na+ Channels (ENaC).,
• More ENaC in the apical membrane, more Na+ reabsorption.

Question 14

Spironolactone

Answer 14

Targets Aldosterone Pathway by antagonising Mineralocortioid Receptors. Decreases Na+ reabsorption in the Collecting Duct.

Question 15

Amiloride

Answer 15

ENaC inhibitor. Decreases Na+ reabsorption in Collecting Duct.

Question 16

Syndrome of Apparent Mineralocorticoid Excess (SAME)

Answer 16

• Mutations in 11betaHSD2 give rise. Also by consuming too much liquorice/glycyrrhetinic acid (but this is not the same as SAME, not as severe).
• Causes severe hypertension.
• Stimulates Na+ reabsorption by allowing circulating Cortisol to activate Glucocorticoid Receptor pathway.

Question 17

Atrial Natriuretic Peptide (ANP)

Answer 17

• Released from cardiac atria when volume receptorsd sense stretch in the atria e.g. when ECV has increased.
• Acts to lower ECV by increasing Na+ excretion (natriuresis) in urine e.g. inhibiting tubular Na+ reabsorption. Which decreases blood volume and pressure.
• Also causes vasodilation to decrease BP.

Question 18

Mechanism of Action of Atrial Natriuretic Peptide

Answer 18

1. GFR increased - haemodynamic effect which changes tubular reabsorption along the length of the tubule.
2. Na+ reabsorption is directly or indirectly inhibited.
3. Angiotensin II stimulated Na+ reabsorption is inhibited - as ANP decreases renin release so therefore decreases RAAS and their (AngII and Aldo) effects are reduced.
4. Na+ load to Loop of Henle is increased.
5. Passive water efflux is decreased in the thin descending limb of the loop of henle.
6. Hypertonicity of the medullary interstitium is decreased.
7. Passive Na+ efflux is decreased in the thin ascending limb of the loop of henle.
8. Load to Macula Densa is increased.
9. Renin secretion is inhibited.
10. Na+ reabsorption is inhibited due to decrease in plasma aldosterone levels caused by ANP inhibiting aldosterone release directly in adrenal gland.
11. Thiazide-sensitive Na+-Cl- Co-transport is inhibited.
12. Na+ load to inner medullary collecting duct is increased.
13. Amiloride-sensitive Na+ reabsorption in Medullary Collecting Duct is inhibited.
14. Furosemide-sensitive Na+-K+-Cl- Co-transport in the basolateral membranes is stimulated.
15. Increased natriuresis and decreased ECV.