L13. Renal physiology 2; nephron train again

Question 1

What happens in the early distal convoluted tubule (/ thick ascending limb known as the diluting segment)

Answer 1

1. There is further transfer of the Na+ and Cl- from the tube into the cell by transporter.
2. Water cannot follow bc of tight junctions

Question 2

How do thiazide diuretics work compared to furosemide diuretics and potassium sparing diuretics (eg. amiloride)

Answer 2

All stop Na+ being reabsorbed so then more stays in the filtrate to be excreted- lowering bp.

Furosemide blocks the NKCC2 in the TAL.

Thiazide diuretics block the Na/Cl transporter in the early distal convoluted tubule .
This leads to more Na+ at the late distal tubule which causes too much K+ loss- hypokalemia which can lead to ventricular arrhythmias.

K sparing diuretics target ElectrogenicNaChannel in the principal cells of late distal convoluted tubule. Another one is spirolactone which blocks aldosterone there.

Question 3

What happens in the late distal convoluted tubule, connecting tubule and collecting duct

Answer 3

• Principle cells reabsorb Na+ and secrete K+ via ENAC and Romk
• Intercalated cells help with acid base balance, K+ and HCO3- absorption. The H+ ions secreted without contributing to HCO3- absorption will make more acidic pH in the Collecting duct.
• cortical collecting duct: water reabsorption depending on ADH/AVP there

Question 4

How do principle cells work.

Answer 4

Na+ reabsorbed into cell by the electrogenic sodium channel (ENAC) making lumen electronegative.
ROMK channel in the apical membrane allows leaking of K+ back to lumen to balance in proportion to the amount of Na+ in the lumen.

Question 5

What is the affect of aldosterone on principal cells vs intercalated cells

Answer 5

Aldosterone enters cell binds to receptor,
Principal cells: upregulates activators that open ENaC channels and then over days induces production of more ENaC and Na/KATPase.

Intercalated cells: directly stimulates the activity of H+ATPase (non genomic) to excrete H+
and indirectly drives H+ secretion through making electronegative lumen due to effects of increased Na+ uptake by ENaC

Question 6

How do intercalated cells work

Answer 6

They secrete H+ ions from the CO2 + H2O reaction via HATPase and H/K+ATPase.
The H+ is used to help HCO3- form back to CO2 and H2O to cross into the cell (help from brush border CA), where it can dissociate again and HCO3- is transported into the ECF

Question 7

How does the kidney help acid base balance and how is diffusion trapping involved

Answer 7

• The acids from food are buffered by HCO3- to become CO2 to be blown off, but this depletes the HCO3- supply.
• If not replaced it will get acidaemia. Therefore when HCO3- is filtered into the urine, it needs to be reclaimed as well as some new HCO3- being made.
• Less chance of acidaemia with secreting H+ in the urine
• The H+ ions secreted in the tubule can join freely diffusible NH3 to form NH4+ which is cannot diffuse back into ECF and is excreted. (diffusion trapping) Cannot get rid of lots of H+ just pumping it out alone

Question 8

How does water reabsorption in the cortical collecting duct work- depending on ADH
(aka AVP)

Answer 8

If Anti-Diuretic Hormone (aka AVP), it binds to basolateral receptor, activates signalling pathway which causes vesicles containing aquaporin water channels to insert in apical membrane RAPidly.
This allows water to be reabsorbed- making urine 300 mOsm (equibrilate).

If no ADH then tubular lumen remains 50 mOsm.

Question 9

How does water reabsorption in the outer medulla collecting duct work (further down the collecting duct)

Answer 9

Outer medulla region has 600 mOSm in ECF, so if ADH, then water reabsorption by aquaporin- concentrated urine.
If no ADH then low water reabsorption, dilute urine.
eg. when large increase in free water- reduced osmolality-> reduce ADH-> high urine flow rate

Question 10

How is the osmotic gradient established in the inner medulla- Long loop nephrons.

(1200 at the bottom, 600 at the top)

Passive hypothesis

Answer 10

1. With High ADH, aquaporins in distal convoluted segments, there is high water reabsorption so [Urea] becomes very high
2. in inner medulla collecting duct, ADH increases urea (and water) permeability- as well as without ADH.
3. Urea moves to the medulla interstitium
4. Water follows the urea into the interstitium and this helps [NaCl] to move out of the tip of the ascending limb down its conc gradient, as well as NaCl from the collecting duct.
5. Countercurrent exchange by the vasa recta helps preserve osmotic gradient and carries the water away.

Question 11

What happens when ADH is low - how does this effect the conc of urea in the medulla interstitium

Answer 11

1. Water is not reabsorped by the distal nephron and the cortical collecting duct so the urea isn’t concentrated.
2. If the [urea] in the interstitium > [urea] in the collecting duct (inner medullar one is still permeable to urea), then urea will diffuse into the collecting duct and be excreted so [urea] in the inner medulla will be low.
3. When ADH is high urea is deposited in the medulla again.

Question 12

How does Chronic kidney disease start from high bp

eg. due to damage from diabetic nephropathy and hypertension.

Answer 12

1. Due to high bp-> mesangial cell expansion-> podocytes fall off BM (non replaceable) -> exposed BM leads to scarring
2. proteinuria
3. substances filtered out damage the tubules causing chronic inflammation, excessive fibrosis and hypoxia- damage to bv.
4. Progressive loss of nephrons
5. Renal failure