Loop of Henle, Distal Tubule and Collecting Duct

Question 1

What are the segments of the LOH?

Answer 1

• thin descending limb
• thin ascending limb
• thick ascending limb

Question 2

What is the major function of the LOH?

Answer 2

counter current multiplication. About 25% NaCl is reabsorbed in this segment by an active transport mechanism.

Question 3

What is the overall function of the DT?

Answer 3

regulated reabsorption of NaCl. About 5% of NaCl is reabsorbed in this segment.

DT converts TF into urine with composition distinctly different from plasma. This function is achieved by specialized and tightly regulated transport characteristics.

Question 4

How is the composition of urine different from plasma?

Answer 4

Osmolarity: 0.2-4.0 fold of plasma

Na+: 0-2% of filtered load

K+, Ca2+, Mg2+: finely regulated

PO4 and H+: maintain pH of urine at 4.5-8.0

Question 5

T or F. Superficial nephrons have short LOHs whereas jutamedullary nephrons have long loops.

Answer 5

T. The thin descending limb of LOH starts at the distal end of PT and runs from cortex to medulla

Question 6

Describe the osmolarity of the fluid in the medulla

Answer 6

The fluid is markedly hyper osmotic compared to plasma. It is isosmotic to plasma at the border between cortex and medulla, but increases progressively downwards to a max of 1200 mOsml/L at the papillary tip (from 280 at the start of the DT).

Question 7

What is the main function of the thin descending limb?

Answer 7

concentration of TF.

Question 8

How does the thin descending limb concentrate the TF?

Answer 8

This is achieved by the unique transport characteristics: no active transport mechanisms.

Highly water permeable (but NaCl impermeable) due to the presence of aquaporins in the epithelial membranes.

Question 9

How does the fluid delivered to the LOH differ from plasma?

Answer 9

similar to plasma, but no protein, no organic solutes, low bicarbonate, slightly higher chloride, urea is about 6 mM.

As this flows down the thin descending limb, water is reabsorbed and the osmolarity of TF increases progressively.

TF hyperosmolarity at the tip of LOH is mainly due to NaCl, but 50-100 mOsm/L is due to urea.

Question 10

What is the main driving force for water reabsorption in the thin descending limb?

Answer 10

Osmotic gradient between the luminal fluid and IF.

Question 11

What aquaporins are present in the TDL?

Answer 11

AQ1 is in PT; AQ in TDL is unclear. AQ1 was thought to play role. But it is present only on long loop nephrons and not in short nephrons.

Question 12

T or F. The structure of thin ascending limb is similar to descending limb

Answer 12

T, but the transport properties are distincly different.

It is water (and urea) impermeable due to absence of aquaporins, and high permeability to NaCl.

Question 13

What drives NaCl reabsoprtion in the ATL?

Answer 13

As the highly concentrated TF flows upwards NaCl is reabsorbed heavily (20-25% of filtered load) due to osmotic gradient

and therefore the Osmolarity of TF decreases as it moves up.

Question 14

T or F. At the bottom of loop there exist a urea concentration gradient between TF and IF.

Answer 14

T. As this of loop is impermeable to urea it helps maintain the osmolarity gradient.

Question 15

How is the structure of the thick limb different from the TDL and TAL?

Answer 15

Unlike thin limbs, the thick ascending limb consists of think epithelium with lots of mitochondria in the cells

Question 16

What is the main function of the thick limb?

Answer 16

The main function is NaCl reasbsorption that occurs by active transport mechanism.

The segment is impermeable to water.

Question 17

What transporters are active in the thick limb?

Answer 17

1) Na-K-2Cl transporter in the luminal membrane of the epithelium. It transports 1 Na+ , 1 K+ and 2 Cl- equivalents from the lumen into cytoplasm, and therefore the transport is electro neutral. The driving force is the electrochemical gradient created by NKA.
2) Basolateral channel NKA, therefore maintains the electrochemical gradient needed for ion transport via Na-K-2Cl transporter.

Question 18

Are there any other channels that facilitate the NaCl transport in the thick limb?

Answer 18

Yes, Apical K channel (ROMK) and BL Cl channels maintain normal steady state ionic balance

Question 19

NK2C is sensitive to what? Why?

Answer 19

diuretics such as furosemide and bumetanide.

They have high affinity to Cl binding site and block the activity of this channel and block NaCl reabsorption.

Result is: Delivery of more NaCl and isotonic fluid into the distal segments, hyperaldosteronism, hypokalemia

Question 20

What is the result of delivery of more NaCl and isotonic fluid into the distal segments?

Answer 20

This interferes with urine concentration causing more fluid excretion, a condition called diuresis.

These loop diuretics are more efficient than other diuretics that act in DT due to high NaCl reabsorption in the loops compared to that in DT.

Question 21

What endogenous hormones/substances can naturally counteract diuresis?

Answer 21

ADH may stimulate NK2C and stimulate NaCl reabsorption and cause opposing effect on diuresis.

Question 22

How many DCT combine to a CD?

Answer 22

6-8.

NOTE: DCT and CD have distinct cell types, but the functions are soe what similar.

Question 23

How much filtered water does the DCT receive? Na, K, and Cl? Urea?

Answer 23

They receive about 10% of filtered water and less than 10% of filtered Na, K and Cl, and 50% of urea.

Question 24

How is Na reabsorbed in the DCT?

Answer 24

Na+ is actively transported across the epithelium causing K+ to be secreted into the lumen

Question 25

Is the amount of Na+ reabsorbed the same as the amount of K+ excreted?

Answer 25

The Na reabsorption is greater than K secretion, and therefore Cl is reabsorbed

The result is: dilution of tubular fluid, if the tubule is impermeable to water.*

Question 26

Why would the water permeability of the DCT be variable?

Answer 26

The water permeability of DCT and CD varies depending on the plasma level of ADH.

If plasma osmolarity is low due to excessive water drinking, the ADH level is low and the water permeability in DCT is low resulting in diuresis.

But, if plasma osmolarity is high due to water deprivation, the ADH level is high and water permeability in the DCT is high resulting in hyperosmotic urine.

Question 27

Two distinct transport mechanisms for Na reabsorption occur in the DCT. What are they?

Answer 27

• Enac.

- Na-Cl co-transporter.

Question 28

How do Enacs work?

Answer 28

Na is transported by diffusion. The driving force is the electrochemical gradient, created by the NKA in the BM that imports 2K+ from the IF as 3Na+ are pumped out to the IF (Na/K ATPase).

NOTE: This channel is present in both DCT and CD.

Question 29

How do the Na-Cl co-transporters work?

Answer 29

This transports one equivalent each of Na and Cl into the epithelial cell and therefore electroneutral transport. This channel is present only in DCT.

NOTE: epithelial K+ and Cl- are pumped together to the IF to maintain gradients of each and some K+ leaks back into the tubular lumen

Question 30

What do diuretics such as amiloride and triamterene do?

Answer 30

block Enacs and, thus, block Na+ reabsorption (and K+ secretion)

Question 31

What do thiazide diuretics do?

Answer 31

block Na-Cl co-transporter to prevent Na reabsorption.

Blocking Na reabsorption results in delivery of more fluid into the distal nephron and more fluid excretion or diuresis.

Question 32

A Lumen-negative transpithelial voltage exists in the DCT and CD due to the activity of electro conductive Na channels removing positively charged Na from the tubular lumen

Answer 32

Na transport via this channel creates more negativity in the lumen causing the membrane to depolarize.

This is more in CD than DCT and plays a role in K+ secretion to both the tubules and IF.

Question 33

T or F. K secretion occurs in the DCT and CD passive diffusion through the apical K channel

Answer 33

T. The driving forces are high intracellular K concentration, and the lumen-negative potential

Question 34

Why is K secretion greater in CD than DCT?

Answer 34

due to higher depolarization in CD.

Other regulatory factors are: fluid flow – higher the fluid flow higher is K secretion.

Na delivery to DT – higher the Na delivery to DCT and CD greater the lumen-negative voltage and greater K secretion.

Question 35

What would be the effects of loop diuretics on K secretion?

Answer 35

increase K secretion (increased Na flow to DCT and CD and therfore higher lumen-negative voltage)

Loop diuretics deliver more Nacl and water into DCT and CD where lumen negative potential becomes higher and therefore, increase K secretion.

Question 36

What would be the effects of amiloride on K secretion?

Answer 36

Decrease K secretion. (reduce lumen-negative voltage, but slightly compensated by increased flow)

Amiloride decrease lumen negativity. Therefore no increase in K secretion.

Question 37

What would be the effects of thiazides on K secretion?

Answer 37

Thiazides: only minimal increase due to increased flow.

Thiazides block electro-neutral Na transport. Therefore, any increase in K secretion is due to increased fluid flow.

Question 38

What is aldosterone and where is it produced?

Answer 38

a mineralocorticoid secreted by the adrenal cortex

Question 39

What is the function of aldosterone?

Answer 39

It is an important regulator of Na reabsorption in the DCT and CD.

The actions of aldosterone include increased Na+ reabsorption and K+ secretion.

Question 40

Where does aldosterone act?

Answer 40

Aldosterone acts exclusively in the DCT and CD.

Question 41

How does aldosterone work?

Answer 41

It is cell permeable and binds to cytosolic and nuclear receptors and regulate gene expression related to Na reabsorption.

Aldosterone increases the expression of electro conducting Na channel, Na-Cl co-transporter, NKA and K channel in the DCT and CD epithelial cells.

It also increases the expression of Kreb’s cycle enzymes and ATP synthesis, all factors needed to increase Na reabsorption and K secretion.

Question 42

What is Addison’s disease?

Answer 42

a condition where there is a complete absence of aldosterone production.

The result is increase excretion of NaCl in the urine. Nearly 2% of filtered load (500mEq/L) of NaCl is excreted in these patients (which means 6-8% is reabsorbed)

Question 43

T or F. Therefore, “Na+ reabsorption and K+ secretion do not entirely depend on aldosterone”

Answer 43

T. See last card

Question 44

What is Conn’s syndrome?

Answer 44

Conn’s syndrome is an opposite condition.

Aldosterone secreting tumors maintain a high plasma level of aldosterone. The result is increased Na reabsorption, and reduced urinary excretion of Na, which is less than 0.2% of filtered load of Na.

Question 45

What is Liddle’s syndrome?

Answer 45

Symptoms are identical to hyperaldosteronism, but plasma aldosterone is normal. AD

Aldosteronism like activity is caused by mutation of electrogenic Na channel so that it is not degraded.

Question 46

How is aldosterone secretion regulated?

Answer 46

Normally aldosterone secretion is regulated by feed back regulation.

Question 47

What conditions favor aldosterone secretion?

Answer 47

• Reduced ECF volume and cardiac output
• Decreased plasma Na+
• Increased plasma K+
• High plasma angiotensin II
• Trauma, stress

Question 48

What conditions don’t favor aldosterone secretion?

Answer 48

• Increased ECF volume
• Increased plasma sodium
• Decreased plasma K+
• Low plasma angiotensin II
• Low plasma ACTH levels

Question 49

What is the treatment for Liddle’s syndrome?

Answer 49

Spironolactone that targets CD Na channel not very effective treatment, but tiamterene that also targets DCT Na channel is more effective in reducing hypokalemia and hypernatremia.

Question 50

Final acidification of urine in the DCT and CD. How?

Answer 50

DCT and CD play role in H+ secretion and HCO3- reabsorption and therefore in regulation of acid-base balance.

Question 51

There are two types of cells in DCT and CD. What are they?

Answer 51

• principal cells involved in Na reabsorption and K secretion.
• alpha and beta intercalated cells, which play role in proton secretion and HCO absorption (or vice-versa)

Question 52

How does proton secretion occur in the DCT and CD in acidic conditions?

Answer 52

Proton secretion is some what similar to that in the PT. This is an active transport process and a different type of proton channel is involved.

In the PT NHE is involved in proton secretion to the lumen, whereas a proton pump is involved in the DT.

Question 53

What proton transporter is used in the DT?

Answer 53

the proton-activated ATPase. The ATP hydrolysis drives the transport of H+ against the concentration gradient from the cell to the lumen.

Proton secretion is coupled to HCO3- reabsorption via HCO-Cl antiport on the BL (CL- is then recycled to the interstitium and some to the lumen)

Under a condition of high acidosis, a-intercalated cells express a new proton transporter. This is HK-ATPase also known as proton pump (K+ is then recycled to the lumen)

Question 54

Under conditions of alkalosis, proton-activated ATPase and HCO3-Cl antiport swith directionality with proton-ATPAse in the basolateral membrane.

Answer 54

There are two types of intercalated cells a and b cells. A-cells have proton channel in the luminal membrane, whereas b-cells have proton channel in basolateral membrane. B cells are activated under conditions of acidosis and alkalosis.

This is just the opposite of card 54.