ICPP 6 - Ion Transport in Renal Physiology & Drug Metabolism

Question 1

What two substances do the proximal tubule cells in the kidney reuptake?

Answer 1

Na+ ions & Bicarbonate ions

Question 2

How are Na+ ions reabsorbed by he proximal tubule and put back into the capillary?
As a consequence, what happens to the filtrate in the lumen?

Answer 2

• Na/K ATPase provides Na+ gradient by removing Na+ from proximal tubule cells (into capillaries)
• Na+ can move into the cell via the Na/H exchanger
• NHE exchanges Na+ for H+ ions which leads to acidification of filtrate in lumen

Question 3

How are bicarbonate ions reabsorbed by the proximal tubule and put back into the capillary?

Answer 3

• H+ ions placed into the lumen from NHE during reabsorption of Na+ combine with HCO3- to form carbonic acid
• Carbonic anhydrase breaks down carbonic acid into CO2 and H20, which diffuse passively into proximal tubule cell
• CO2 + H20 reform carbonic acid which is broken down by carbonic anhydrase again to form H+ and HCO3- ions.
• HCO3- ions reabsorbed into capillary by anion exchanger (AE) and H+ back into filtrate via NHE.

Question 4

Why does the kidney reabsorb all the HCO3- ions into the proximal tubule?

Answer 4

As it retains base which is vital for pH buffering in the body.

Question 5

What is renal control of circulating Na+ concentration a 1st line treatment for?

Answer 5

Mild hypertension (diuretics).

Question 6

How does amiloride block Na+ reuptake by the proximal tubule and work as a diuretic/antihypertensive?

Answer 6

It blocks the NHE which prevents Na+ from reaching proximal tubule. Instead it continues its journey into urine, and as it is an osmolyte it brings water with it (thus reducing BP).

Question 7

Why is amiloride most likely not a 1st line antihypertensive?

Answer 7

As it blocks the NHE it also blocks bicarbonate reabsorption which would have adverse effects on body buffering.

Question 8

How is Na+ reabsorbed in the thick ascending limb?

Answer 8

• Na/K ATPase creates Na+ concentration gradient
• Allows Na+ to move in via the NaK2Cl co-transporter
• Na+ can move back into capillary via Na/K ATPase

Question 9

What drug class inhibits the NaK2Cl co-transporter in the TAL and is a 1st choice drug for mild hypertension?

Answer 9

Loop Diuretics

Question 10

How is Na+ reuptaken in the distal convoluted tubule?

Answer 10

• Na/K ATPase creates Na+ gradient for reabsorption of Na+ via the NaCl co-transporter
• Also via ENaC which allows Na+ to enter via the gradient produced by Na/K ATPase

Question 11

What is the NaCl co-transporter + ENaC in the DCT inhibited by?

Answer 11

NaCl = Thiazides (1st line for mild hypertension)
ENaC = Amiloride

Question 12

How is Ca2+ reuptaken in the DCT of the kidney?

Answer 12

• NCX extrudes Ca2+ into blood and creates gradient for movement of calcium into DCT via TRPM6 channels.

Question 13

What are organic anion transporters (OAT’s)?

Answer 13

• Polyspecific anionic substrate transporters - 11 family members. They are Tertiary AT’s

Question 14

How do OAT mediate transport of OA’s in the proximal tubule and eventually lumen from the blood?

Answer 14

• Na gradient produced via Na/K ATPase
• Drives the uptake of dicarboxylate into the proximal tubule cell from the capillary
• This drives transport of organic anions into proximal tubule cell via OAT’s as they remove the dicarboxylate
• They can then enter filtrate in lumen via a host of channels, e.g.: MRP2 + 4

Question 15

By regulating key metabolites and signalling molecules, what roles do OAT’s play a key part in?

Answer 15

1) Whole organism homeostasis
2) Interorgan communication
3) Interorganismal communication - e.g.: breast milk, placental barrier + odorants in urine

Question 16

What are organic cation transporters?

Answer 16

Polyspecific cationic substrate transporters - 6 family members (OCT 1-3, MATE 1-2, PMAT)

Question 17

How do OCT’s mediate uptake of organic cations into PT and then the lumen?

Answer 17

1) Organic cations transport from capillary to PT cell driven by electrochemical gradient via OCT2 channel (as it is more negative within the cell)
2) cation transport from PT cell to lumen via MATE2 driven by pH gradient (more acidic in the urine in lumen and therefore swaps OC’s for H+)

Question 18

How do organic cation transporters affect drug availability, e.g.: of metformin?

Answer 18

• Metformin decreases hepatic glucose production in type 2 diabetes
• Patients w/polymorphism for OCT1 have reduced activity
• Hepatic uptake of metformin reduced, reducing anti-diabetic effect.

Question 19

How do OCT’s such as OCT2 and MATE2 cause toxic drug accumulation? - use cisplatin as an example.

Answer 19

• Cisplatin is excellent substrate for OCT2 therefore is well taken up into proximal tubule cell from capillary
• Cisplatin is a poor substrate for MATE1/2
• Therefore cannot be excreted into urine in lumen and accumulates in cell leading to drug toxicity/nephrotoxicity.