Renal regulation of potassium

[REVIEW] Physiological role of intracellular and extracellular potassium

Describe the Two Regulatory Mechanism of K+

1. Cellular K⁺ uptake

   • Occurs within minutes after a meal.

   • K⁺ is rapidly shifted from the ECF into cells, reducing plasma K⁺ levels.

2. Renal excretion:

   • Occurs over hours.

   • Kidneys excrete excess K⁺ to maintain long-term balance

1. What is the normal range of Potassium in the Body? Distribution of ECF/ICF

2. Describe the Causes of Hypo/Hyper Kalemia

3. Describe how these factors can affect K+ levels:

   1. Acid-Base Disorders

   2. Plasma Osmolality

   3. Cell Lysis/Vigorous exercise

Physiology of potassium balance:

• Normal Level: 3.5–5.0 mEq/L

• 98% = ICF; 2% = ECF

---

Hypokalemia Causes:

• Diuretic,

• vomiting,

• genetic defects in distal tubule Na⁺/Cl⁻ symporters

HyperKalemia:

• Renal failure,

• ACE inhibitors,

• K⁺-sparing diuretics,

• dietary K⁺ supplements

---

Modulating Factors:

• Acid-Base Disorders:

  • Acidosis → ↑ plasma K⁺ (H⁺ “in”, K⁺ “out” of cells)

  • Alkalosis → ↓ plasma K

• Plasma osmolality:

  • ↑ osmolality → ↑ K⁺ efflux

• Cell lysis & vigorous exercise → ↑ K⁺ plasma (due to the release of intracellular K⁺ )

Describe Cellular K+ Uptake:

• Key transporters?

• Hormonal Regulation

• Systemic Coordination

Key Transporters:

• Na⁺/K⁺-ATPase:

• NKCC (Na⁺-K⁺-2Cl⁻ cotransporter):

---

Hormonal Regulation:

• Insulin: Stimulates Na⁺/K⁺-ATPase activity and glucose uptake via GLUT4.

• Catecholamines (e.g., epinephrine):

  • (β₂-AR) activate cAMP signaling, enhancing K⁺
    uptake (reabsorption).

  • α-AR inhibits insulin release, while β₂-AR stimulates insulin secretion.

• Aldosterone: Binds MR → increasing Na⁺/K⁺-ATPase
  expression.

---

Systemic Coordination:

• Pancreas (β cells): Releases insulin in response to β₂-AR stimulation.

• Adrenal gland: Produces aldosterone (cortex) and epinephrine (medulla) during acute changes in plasma K⁺

Describe the mechanism in which Acidosis causes Hyperkalemia

Mechanism:

• Low pH → Inhibits Na/H Exchanger and Na/HCO3- Cotransporter → Reduced intracellular Na+ and High H+ inhibits Na/K ATPase and NKCC → Slows down K+ Uptake

• Increased H+ Intracellular levels → Displaces K+ from its intracellular binding sites → promote K+ Exit

1. Describe how K+ Excretion Varies

2. Where is K+ Secreted?

K+ Excretion:

• K+ depletion (~0%- 2%)

• Normal K+ intake (15-80%)

• Increased K+ intake (up to 150% of filtered load)

---

K+ Secretion:

• DT/ Cortical CD: Principle Cells

Draw out K+ Transport @ PT/ TAL

Describe K+ Transport in DT and CD

Alpha-intercalated cells

• reabsorb K+/ Secrete H+

• Activated by Low K+

• Transporters: Via K,H ATPase and H-ATPase

---

Principal cells:

• secrete K

• Main Determinants = Na+ delivery to the DT→ Reabsorption via ENaC→ Electrochemical Gradient (More positive intracellular, less out, K+ leaves Cell)

• Transporters: K,Cl-symporter, K- channels (multiple: ROMK and BK)

Describe Regulation of K + secretion by the distal tubules and collecting ducts

• What are the Three mechanisms that governs K+ Secretion in DT/CCD

• What physiological factors regulate K+ Excretion (4)

• Pathophysiologic Factors?

The mechanism of K + secretion by the DT and CCD:

• Na,K-ATPase activity and Na⁺ reabsorption:

  • Maintains intracellular [K⁺] → creates electrochemical gradient for K⁺ secretion

• Electrochemical Gradient: Drives K⁺ movement through K⁺ channels and K⁺/Cl⁻ symporters

• Apical membrane K⁺ permeability

  • ROMK (Renal Outer Medullary K⁺ channels)

  • BK ( (“Big” K channels, Ca²⁺-activated, “big” – large-conductance calcium-activated potassium channels)

---

Physiologic factors that regulate K excretion:

• Plasma K⁺ concentration: Directly influences K⁺ secretion rate.

• Aldosterone: Enhances Na⁺ reabsorption and K⁺ secretion.

• Angiotensin II: Inhibits ROMK channel activity, decreases K⁺ secretion.

• Arginine Vasopressin (AVP): Modulates water and electrolyte balance, indirectly affecting K⁺ excretion.

---

Pathophysiologic factors:

• Flow rate of tubule fluid

• Diuretics: loop (inhibitors of NKCC), thiazides (inhibitors of NaCl symporter), and osmotic diuretics stimulate K+
  excretion

• Acid-base disorders.

Differentiate between ROMK and BK

ROMK vs BK:

• Both Secrete K+

• Activation:

  • ROMK mediates routine K⁺ secretion,

  • BK channels are recruited during high K⁺ loads or increased flow states

• Regulation:

  • ROMK:

    • Upregulation via aldosterone

    • inhibited by Ang II and AVP.

  • BK:

    • Strongly flow-dependent;

    • activated by high K⁺ and aldosterone.

  • High plasma K⁺: Stimulates both channels to enhance K⁺ secretion.

Describe how Na+ delivery to the principal cells regulates K+ secretion

1. Na⁺ Reabsorption: Na⁺ enters principal cells via ENaC channels, following its electrochemical gradient.
   

2. Na⁺/K⁺ ATPase: pump moves 3 Na⁺ out / 2 K⁺ in → maintaining low intracellular Na⁺ and high K⁺.
   

3. Electrochemical Gradient: This active transport creates positive Voltage inside Cell/ and Less Positive in Tubular Lumen

4. K⁺ Secretion: lumen-negative potential drives K⁺ efflux into the tubular fluid through apical K⁺ channels

Describe how High K+ Dietary Levels lead to Kidney Modification (increased K+ Excretion)

• Mechanism in Late DT/Cortical CD

• Supporting role in PT, TAL, DT

How does the Body sense High K+ levels?

Primary Site of Action of this modification (enhanced K+ Excretion): in Late DT/Cortical CD

---

Mechanism in Late DT/Cortical CD:

• ↑ Na⁺ reabsorption → electrochemical gradient → K⁺ secretion

• High plasma K⁺ → aldosterone secretion, which:

  • Upregulates Na⁺/K⁺-ATPase

  • Increases ENaC channels \

  • Increases # of K⁺ channels for secretion.

• ↑ Tubular flow rate → detected by cilium in principal cells → ↑ intracellular [Ca + +] → opens BK channels

---

Supporting Role in PT, TAL, early DT:

• High plasma K⁺ reduces Na⁺ reabsorption (=enhances Na+ reabsorption in DT/CD)

• Mechanism on how K+ inhibits Na+ reabsorption:

  • Inhibition of Na⁺/H⁺ exchanger

  • Inhibition of NKCC

  • Chronic High K+ Intake:

    • decreased expression of Na⁺/H⁺ and NCC

---

K+ Detection: zona glomerulosa cells

• have resting membrane potentials that are highly sensitive to extracellular K⁺

• K+ Increases → Opens VG Ca++ channels → Aldosterone Release/Synthesis

What is the Effect of AVP on K+ secretion by the DT and CD

NET Effect: AVP does not change overall urinary K⁺ excretion (K⁺ secretion remains constant)

---

Stimulation of K+ Secretion:

• increases Na⁺ conductance → depolarizes
  apical membrane → ↑ driving force for K⁺ efflux.

• increases apical K⁺ permeability → ↑ K⁺ secretion.

---

Inhibition:

• AVP reduces tubular fluid flow → ↓ K⁺ secretion

Compare the effects of Acute vs Chronic Acidosis on K+

How do these factors impact K+ secretion in distal Nephron:

• Low Potassium Diet

• ANG II

• High Potassium Diet

• High Na+ Delivery to principal Cells

• Aldosterone

• High Plasma K+

Describe how These conditions impact Distal K+ secretion (hint: all conditions increases/Decreases K+ Secretion):

• Acidosis

• Volume Expansion

• High Water Intake (water diuresis)

• Volume contraction