Renal Tubular Function 2 L06

Question 1

Name the sections of the loop of Henle.

Answer 1

1. descending limb
2. thin ascending limb*
3. thick ascending limb

*less important functionally than other two sections

Question 2

Is the loop of Henle situated in the renal cortex or medulla?

Answer 2

renal medulla

Question 3

What is the function of the descending limb in the loop of Henle?

Answer 3

• mainly paracellular water transport due to osmotic force
• water moves from filtrate into interstitial space

*salts not absorbed so salt concentrations remain relatively the same at the start and the end of the limb

Question 4

What is the main function of the thick ascending limb?

Answer 4

pumps salts out (Na+ and Cl-) to create a hyperosmolar environment in the interstitial space in the medulla to drive water loss from the descending limb and collecting duct.

Question 5

describe the mechanisms through which ions are transported filtrate into the interstitial space in the thick ascending limb.

Answer 5

Apical membrane:

• Na+/K+/2Cl- transporter (NKCC2)
• apical K+ channels for K+ recycling back into filtrate

Cell:

• low Na+ concentration in
• High K+ concentration
• high Cl- concentration

Basolateral membrane:

• Na+/K+ exchanger actively transports 3Na+ out of cell into interstitial fluid (and 2K+ in)
• basolateral K+ channels facilitate passive diffusion of K+ into interstitial space (then it is reused in Na+/K+ exchanger)
• basolateral Cl- channels facilitate passive diffusion of Cl- into interstitial space following Na+ reabsorption

Question 6

Why is K+ recycled on the apical membrane of the thick ascending limb?

Answer 6

• K+ recycled through apical K+ channels
• K+ moves back into filtrate down electrochemical gradient
• K+ recycling helps to drive Na+ absorption through the NKCC2 transporter as Na+ concentration in filtrate (140mM) much greater than K+ concentration (4mM). If there was no K+ recycling, transporter would run out of K+ very rapidly and would not be able to transport Na+ (or Cl-) across membrane.

Question 7

What is the NKCC2 transporter and how does it work at the thick ascending limb?

Answer 7

Na+/K+/2Cl- transporter (NKCC2)

• ‘cation-coupled chloride transporter’
• moves ions from filtrate into epithelial cell
• Na+ moves down electrochemical gradient
• K+ moves against gradient
• Cl- moves against gradient
• transporter is electrically neutral - 2+ve charges and 2 -ve charges

Question 8

Describe the movement of water through the thick ascending limb.

Answer 8

There isn’t any. Thick ascending limb is impermeable to water - many tight junctions to stop paracellular movement of water from filtrate into interstitial space

Question 9

The thick ascending limb helps to produce an osmotic gradient of…

Answer 9

200mOsm/kg

Question 10

What gene codes for the NKCC2 transporter protein?

Answer 10

SLC12A1

Question 11

What is Furosemide and how does it work?

Answer 11

-diuretic which acts in the loop of Henle
-Blocks NKCC2 transporter
> natriuresis (large amount of Na+ in urine) and diuresis (increased urine)

Question 12

What pathological conditions is Furosemide used for?

Answer 12

renal failure, cardiac failure

Question 13

What are the side effects of Furosemide?

Answer 13

• hypokalaemia –> cardiac dysrhythmias
• hypovolaemia
• mild metabolic acidosis (excess Na+ in urine leads to increased H+ in blood through distal Na+/H+ exchanger)
• loss of Mg2+ and Ca2+ (K+ recylcing helps reabsorption of Mg2+ and Ca2+)

Question 14

Explain the countercurrent multiplier for osmolality and how it maximises reabsorption of water in the loop of Henle.

Answer 14

• descending limb permeable to water but impermeable to ions (NaCl)
• thick ascending limb permeable to ions (NaCl) but impermeable to water
• thick ascending limb pumps Na+ and Cl- into interstitial fluid
• increases osmolalilty of interstital space (more concentrated)
• filtrate initially has osmolality of 285mOsm (equivalent to plasma osmolality *remember Na+ and water reabsorbed at same rate along PT)
• as filtrate moves through descending limb, water moves into interstitium down a water potential gradient (created by the pumping of ions from thick ascending limb)
• osmolality of filtrate increases through the descending up until the tip of the loop where the osmolality of the interstitium and filtrate become equal
• osmolality at the tip of loop (deep in the medulla) is very high (1200mOsm)
• at this point there is no net movement of water into the interstitium
• as filtrate moves up thick ascending limb, the osmolality decreases due to the movement of IONS into the interstitium (remember - water impermeable!)
• this mechanism therefore maximises absorption of water from descending limb AND absorption of ions from thick ascending limb.*

*if there was no countercurrent mechanism (i.e. no water impermeability in ascending limb), there would be less reabsorption of water and ions. This is because osmolality of interstitium and tubule would become equal very early on (start of loop) so no gradient for water/ions to move into interstitium. More water would remain in the filtrate triggering greater release of ADH distally which would not be effective for the body and still result in a greater overall loss of water/ions.

Question 15

How is Na+ absorbed from the distal tubule?

Answer 15

apical membrane:
-Na+/Cl- cotransporter (Na+ moves into cell down e-c gradient)

basolateral membrane

• Na+/K+ pump actively transports Na+ into intersitium
• also K+/Cl- cotransporter transferring K+ and Cl- out of the cell

Question 16

what are the uses of thiazides and their mechanism of action?

Answer 16

diuretic - used as antihypertensive (in conjunction with furosemide)

Act in distal tubule by blocking Na+/Cl- cotransporter > ions not reabsorbed from filtrate > water not reabsorbed from filtrate

*side effects include increased uric acid, hyperglycaemia and hyponatraemia

Question 17

How is water reabsorbed from the collecting ducts?

Answer 17

AQP2 channels at apical membrane and AQP3 channels at basolateral membrane

Question 18

What effect does ADH have on the reabsorption of water in collecting ducts? How is this achieved?

Answer 18

increases reabsorption of water from filtrate

increases number of AQP2 channels on apical membrane

Question 19

How does aldosterone affect Na+ reabsorption at the collecting ducts?

Answer 19

Increases reabsorption of Na+ by stimulating the synthesis of:

• ENaC channels at apical membrane (Na+ travels down gradient into cell)
• Na+/K+ antiporter at basolateral membrane (Na+ actively transported into medullary interstitial space)

Question 20

What is amiloride? How does it work?

Answer 20

-potassium-sparing diuretic (prevents secretion of K+ into urine)
-inhibits ENaC channels in collecting ducts
>no absorption of Na+ from filtrate
>inactive Na+/K+ pump
>no secretion of K+ into filtrate

Question 21

What is the effect of spironolactone (diuretic) in the collecting ducts?

Answer 21

-blocks effect of aldosterone
>no synthesis of ENaC channels or Na+/K+ pump
>no reabsorption of Na+ from duct

Question 22

What is the drug spironolactone used for?

Answer 22

heart failure (K+ sparing diuretic - given to patients with hypokalaemia)

*side effects include gynaecomastia (enlargement of breasts in male), menstrual disorders, testicular atrophy, hyperkalaemia

Question 23

Explain how the urea countercurrent mechanism aids water reabsorption in the medulla.

Answer 23

• late distal tubule and cortical collecting ducts are urea-impermeable
• as water moves out of duct, urea concentration increases
• urea permeability increased in medullary collecting duct due to ADH which increases expression of urea-transporter A1 (UT-A1)
• urea diffuses out of duct due to high concentration build up in tubule
• urea helps to increase osmotic pressure in medullary interstitium
• more water reabsorbed from loop of Henle and collecting duct.