Week 2: Renal and muscle regulation of K+ balance

Question 1

Describe the K+ distribution in ECF vs. ICF and the role of Na/K ATPase and pH in influencing the distribution.

Answer 1

• 98% ICF (mainly muscles) and 2% ECF

- Na/K ATPase maintains large concentration difference

Question 2

Compare effects of potassium rich meal, insulin, epinephrine, and potassium deprivation on K+ transport into muscle ICF?

Answer 2

• Potassium rich meal: stimulates insulin secretion from pancreas
• insulin: stimulates K+ uptake into cell by increasing Na/K ATPase activity
• epinephrine: a-adrenoceptors releases K+ from cells, stimulation of b2-adrenceptors promotes K+ uptake by cells
• Catecholamines: exercise increases K+ in EF, needs to be cleared back into ICF. Catecholamines can activate Na/K ATPase during exercise, and exercising muscles can adapt to release less K+ as cell ATP falls
• low K+: decrease in number of Na/K ATPase muscle cells, less K+ pumped in. Less K+ secretion by distal nephron. Buffers fall in plasma K+.

Question 3

How do changes in acid-base balance alter plasma [K+}?

Answer 3

METABOLIC ACIDOSIS
—>Increases plasma [K+]. Reduced pH promotes movement of H+ into cells and movement of K+ out to maintain electro neutrality. H+ displaces K+’s assoc. with - charged proteins inside cell. Acidosis also inhibits Na/K ATPase and NK2Cl symporter.
—>chronic: decreases plasma K+. inhibit proximal Na, Cl, water reabsorption. increase flow rate to distal nephron, decreased tubular fluid K+, increase K secretion, excretion
METABOLIC ALKALOSIS
-Decreases plasma [K+]. As H+ moves out of the cell, K+ moves in. Increased ICF[K+] increases gradient for K+ secretion and excretion–>hypokalemia

Question 4

What are factors that alter plasma [K+] that aren’t involved in regulation?

Answer 4

• acid-base balance
• plasma osmolality
• cell lysis: burns, trauma. causes release of intracellular K+.
• Exercise: transient hyperkalemia. exercise increases K+ in EF, needs to be cleared back into ICF. Catecholamines can activate Na/K ATPase during exercise, and exercising muscles can adapt to release less K+ as cell ATP falls

Question 5

Describe handling of K+ along proximal tubule. and loop of Henle.

Answer 5

• PT: reabsorbs 2/3 of filter K+
• Loop of Henle: ~20% filtered load reabsorbed via apical NaK2Cl in TALH. Those most of this is recycled via apical K+ channels

Question 6

Describe cellular mechanism of K+ secretion in the distal tubule and collecting duct.

Answer 6

PRINCIPAL cells
1. Na/K ATPase uptakes K+ from blood across basolateral membrane
2. creates high [K+] intracellularly, driving force for K+ to excite across apical membrane through K+ channels (ROM K).
3. Permeability of K+ in apical membrane greater than asolateral
4. K secretion driven by ENaC mediated Na reabsorption (Na from tubule lumen into cell, leaves to blood via Na/K ATPase)
INTERCALATED cells
1. Apical H+/K+ATPase may facilitate K+ uptake
2. electrochemical potential favors secretion, net absorption must be ACTIVE
3. H+-ATPase for acid base
4. flow sensitive K channels- activity will increase if there is less Na reabsorbed before CD

Question 7

How does K+ excretion/reabsorption in CD vary with low, normal, and high K+ diet? Describe cellular mechanisms behind these changes.

Answer 7

1. Normal: Net Secretion
   - ~20% leaves CD
   - ROM K channels insert into apical membrane for secretion in CD
2. Low: net reabsorption
   - 1% leaves CD, 99% filtered load reabsorbed
   - ROM K channels retract out of apical membrane in principal cells but aren’t degraded. Ready to move back after eating K+ rich meal
   - decreased apical K+ channel activity (K+ out) and increased HK-ATPase activity in intercalated cells (K+ in)
3. High: Net Secretion
   - up to 80% leaves CD
   - ROM K channels insert into apical membrane in CD
   - tissue kallekrein secreted from CT cells inactivates HK ATPase (prevents K+ coming in from tubule lumen on apical side)

Question 8

What are luminal factors affecting potassium transport in cortical collecting tubule and ducts?

Answer 8

FAVOR SECRETION INTO TUBULE FLUID
-high ICF [K+] or low tubule fluid [K+]: increases gradient
-high [Na+] in TF: increases reabsorption by ENaC, increases electrochemical gradient
-high Na deliver in TF by increasing flow
-high [HCO3-] in TF: increases electrochemical driving force for K+ since HCO3- is poorly reabsorbed anion in TF
-low [Cl-] in TF: assoc. with increase in poorly reabsorbed anions in TF
DOESN’T FAVOR SECRETION
-ENaC inhibitors: less Na+ reabsorbed decreases electrochemical gradient. Can lead to hyperkalemia

Question 9

What are peritubular factors that affect potassium transport in cortical collecting tubule and ducts?

Answer 9

FAVOR SECRETION INTO TUBULE FLUID
-high ECF [K+] –>high ICF[K+] : hyperkalemia stimulates Na/K ATPase, increases K uptake, raises ICF [K+]. Increases gradient for K+ secretion. high ECF [K+] also stimulates aldosterone secretion
-alkalemia–> high ICF [K+], increases gradient driving secretion
DOESN’T FAVOR SECRETION
-low ECF[K+] –> low ICF[K+] : decreases gradient driving K secretion into TF. Lower ECF [K+] also increases HK ATPase
VARIABLE
-acidemia

Question 10

How do diuretics lead to more K+ secretion?

Answer 10

• diuretics that act before CT block sodium transporters and increase volume flow to the collecting tubules
• increase Na+ deliver leads to increased Na+ reabsorption via ENaC, which is associated with increased K+ and H+ secretion through ROM K channels and H-ATPase.

Question 11

Describe effect of aldosterone on K+ secretion.

Answer 11

-decreased ECF volume and increased plasma [K+] lead to aldosterone production which has the following effects.
1. Increases Na/K ATPase on basolateral membrane
2. Increases ENaC activity on apical membrane.
These drive K+ and H+ secretion into tubule fluid.
-Chronically lower ECF volume with increased aldosterone can lead to hypokalemia and alkalosis known as contraction alkalosis.
-acute increase in aldosterone levels don’t increase K+ excretion b/c aldosterone stimulates Na+ and water reabsorption, decreasing tubular flow

Question 12

Discuss what happens in response to acute increase in dietary K+.

Answer 12

Sequence of events:

1. upon ingestion, K+ absorbed across gut into ECF. Stimulation of Na/K ATPase by insulin–> uptake to ICF
2. ICF K+ released back to ECF during muscle activity and filtered into kidney
3. K+ excretion stimulated after acute K+ ingestion by rise in plasma [K+] or signal initiated by gut
   - also increased plasma[K+] –> dephosphorylation of NCC in distal convoluted tubule (aldosterone probably not involved)
   - downward shift in Na+ to cortical connecting and collecting ducts, where ENAC generates lumen negative potential to increase driving force for K+ secretion