[OS 206] E03-T06-Tubular Reabsorption of Electrolytes (Na, K, Ca, Mg, HCO3)_compressed

• Excretion of solute = glomerular filtration + secretion - reabsorption

Sodium Reabsorption in Proximal Convoluted Tubule (PCT)

• Sodium is the major cation or electrolyte of the extracellular fluid (ECF)
• Dictates ECF volume, which determines plasma volume, blood volume, and blood pressure
• Where sodium goes, water follows
• PCT reabsorbs 67% of the filtered sodium, the major site of reabsorption for many other solutes
• Early PCT: Sodium is reabsorbed primarily with bicarbonate & organic solutes (glucose and amino acids)
• Late PCT: Sodium is reabsorbed primarily with chloride, but lacks organic solutes
• Isosmotic reabsorption involves tight coupling between sodium and water reabsorption, crucial for maintaining ECF volume
• Glomerulotubular balance in the proximal tubule couples reabsorption to glomerular filtration rate (GFR), maintaining a constant proportion reabsorbed with GFR changes
• Reabsorption in the PCT isn't constant. An increased GFR will lead to a higher amount of sodium delivered to the tubules, and can overwhelm the PCT’s reabsorptive capacity, leading to excretion of the remainder in the urine.

Sodium Reabsorption in Early PCT

• Na+ reabsorbed together with most essential solutes.
• Glucose, amino acids, and bicarbonate (HCO3−) among the key solutes
• The above solutes should not be in the urine
• Sodium transport in the luminal membrane of early PCT:
  • Na+-glucose (SGLT2) cotransport
    • SGLT2 inhibitor drugs (e.g., empagliflozin, ertugliflozin) prescribed for diabetic / heart failure patients to promote glucose excretion, thereby lowing blood glucose levels.
    • Can increase risk of UTI
  • Na+-amino acid cotransport
  • Na+-phosphate cotransport
  • Na+-lactate cotransport
  • Na+-citrate cotransport
  • Na+-H+ exchange (NHE) countertransport

Sodium Reabsorption in Late PCT

• Late PCT reabsorbs primarily NaCl
• Na+-H+ exchanger transporter
• Cl−-formate anion exchanger
• Na+ goes into blood by the Na+-K+ ATPase, and Cl− moves by diffusion
• Chloride concentration gradient, drives chloride diffusion from lumen to blood and establishes a diffusion potential.
• Na+ reabsorption is then followed, plus paracellular transport of Na+ and chloride.
• Isosmotic fluid accumulates in lateral intercellular spaces, acted upon by Starling forces in the peritubular capillary.

Glomerulotubular Balance

• Ensures that a constant fraction or proportion of the filtered load is reabsorbed by the proximal tubule (normally at 67%)
• Occurs when increased oncotic pressure in peritubular capillaries, increases reabsorption

Sodium Reabsorption in Thin Descending and Ascending Limb of the Loop of Henle

• Thin descending limb is permeable to water and small solutes such as NaCl and urea.
• Thin ascending limb is also permeable to NaCl, but impermeable to water.

Sodium Reabsorption in Thick Ascending Limb of Loop of Henle

• Reabsorbs ~25% of the filtered Na+ by active mechanism that is load dependent
• Contains an Na+-K+-2Cl− cotransporter (NK2CC), target of the loop diuretic Furosemide
• Impermeable to water, making it a diluting segment

Loop Diuretics

• Work on NK2CC (specifically Chloride)
• Furosemide (example) binds to the chloride-binding domain, which Inhibits the NK2CC transporter
• Patient will lose water and sodium, and bivalent ions
• Risk of hypotension
• Risk of hypokalemia, as more sodium is transported to the collecting duct, triggering potassium secretion
• Can lead to metabolic alkalosis through activation of the Na+-H+ exchanger

Sodium Reabsorption in Distal Convoluted Tubule (DCT) and Collecting Duct

• Distal tubule and collecting duct make up terminal nephron, and reabsorb ~8% of the filtered Na+, dependent on load
• The early DCT reabsorbs 5%, and contains a Na+-Cl− cotransporter in the luminal membrane.
• The collecting duct (the fine tuning location) usually reabsorbs 3%

Sodium Reabsorption in Early Distal Convoluted Tubule (DCT)

• Na+-Cl− cotransporter is a target of Thiazide diuretics, impermeable to water, it’s a cortical diluting segment

Thiazide Diuretics

• Targets Chloride via the Na+-Cl− cotransporter
• Can result in:
  • Hypokalemia
  • Metabolic Alkalosis
  • Hypercalcemia

Sodium Reabsorption in Late DCT and Collecting Duct

• Reabsorb only 3% of the filtered Na+
• Principal cells are involved in sodium, potassium and water reabsorption
• Luminal membrane of principal cells contains Na+ channels (epithelial Na+ channels, or ENaC) channels, hormonally regulated by aldosterone

Potassium-Sparing Diuretics

• Usually given with other diuretics to prevent hypokalemia
• Amiloride, triamterene, spironolactone are examples
• Spironolactone prevent aldosterone from entering the nucleus of the principal cells and stops new protein synthesis
• Amiloride and triamterene block the aldosterone-induced increase in Na+ reabsorption.

Glucose Reabsorption

• Almost 100% reabsorbed in proximal convoluted tubule (PCT) via secondary active transport with Na+
• Luminal membrane contains the Na+-glucose cotransporter
• Peritubular (or basolateral) membrane contains the Na+-K+-ATPase, and facilitated glucose transporter
• Glucose transporters are saturable.
  • Plasma glucose concentration <200 mg/dL - All filtered can be reabsorbed
  • Plasma glucose concentration >350mg/dL - All excess sugar is excreted in urine because carriers are saturated

Clinical Physiology: Glucosuria

• Presence of glucose in urine, associated with diabetic patients with uncontrolled diabetes mellitus
• Filtered load of glucose exceeds the reabsorptive capacity (plasma glucose concentration above the Tm), urine excretes the excess glucose
• I.e. Human Placental Lactogen (HPL) during pregnancy increases increases availability of glucose, warranting 75g OGTT to test for gestational diabetes mellitus (GDM)
• Congenital abnormalities involving Na+-glucose cotransporter are also associated with decreased Tm
• Polyuria, Polydipsia, and Polyphagia are other conditions associated with diabetes

Bicarbonate Reabsorption

• Kidneys 2 major roles in the maintenance of of normal acid-base balance:
• Reabsorbs filtered HCO3
• Excrete fixed H+ produced from protein and phospholipid catabolism
• Most filtered HCO3 reabsorption occurs in the proximal tubule; and NO the acid is secreted in the PCTs
• Na+-H+ Exchanger, Na+-HCO3 cotransporter (NBC), and Cl-HCO3 exchanger (CBE) are key transporters
• In lumen, excreted H+ binds filtered HCO3, forming carbonic acid (H₂CO₃) acted upon by the brush border carbonic anhydrase
• CO₂ can readily cross the luminal membrane and enter the proximal tubule cell, where it is converted back into H2CO3
• H2CO3 decomposes into H+ and HCO3, which is reabsorbed back into the blood at the basolateral membrane through NBC and BCE

Factors Affecting Bicarbonate Reabsorption

• Among many filtered loads, virtually all of the HCO3 is reabsorbed as long as the plasma HCO3 concentration is <40 mEq/L
• ECF volume expansion inhibits isosmotic reabsorption in the proximal tubule, inhibiting HCO3− reabsorption
• ECF volume contraction stimulates reabsorption via the RAAS and Angiotensin II

Potassium Reabsorption

• Primarily occurs mostly in PCTs
• In the terminal nephron, dietary concentrations, aldosterone, presence of acidosis/alkalosis, the flow rate and luminal anions determine potassium reabsorption

Potassium Reabsorption in PCT

• Reabsorbs ~67% of the filtered load of K+ by solvent drag, a paracellular mechanism directly proportional to water and Na+ movement

Potassium Reabsorption in Thick Ascending Limb of Loop of Henle

• Reabsorbs 20% via the NK2CC
• Not all reabsorbed K is transported to the basolateral membrane, leaks back into the lumen through apical K+ channels, creating a lumen-positive transepithelial potential
• Electrochemical gradient facilitates the paracellular reabsorption of divalent cations (e.g., Ca2+ and Mg2+).

Potassium Reabsorption in Late DCT and Collecting Ducts

• Responsible for the adjustments in K+ excretion when dietary K+ varies.
• Either Reabsorbs or secrete K+
• Potassium will be reabsorbed by the a-intercalated cells of the late DCT and collecting ducts with the H+-K+ATPase
• Transports H+ from the cell to the lumen, and K+ from the lumen into the cell

Calcium Reabsorption

• Most of the body's Calcium (Ca2+) is contained in the bone (99%),
• The rest 1% sits in ICF and ECF

Calcium Reabsorption in PCT

• The total Ca2+ concentration in plasma is 5 mEq/L or 10 mg/dL, 50% is in the free, ionized form
• Plasma Ca2+ concentration regulated by PTH
• With 67% of the filtered load reabsorbed, calcium will parallel Na+ reabsorption in the PCT through NHE3

Calcium Reabsorption in Thick Ascending Limb of the Loop of Henle

• The NK2CC will create a lumen-positive potential
• Drives the reabsorption of divalent cations such as Ca2+ along the paracellular route

Calcium Reabsorption in DCT

• Reabsorbs ~8% of the filtered load of Ca2+. Unlike sodium being dependent, this calcium reabsorption isn't directly coupled
• Has own regulatory hormone, the thiazide diuretics
• Thiazide diuretics increase reabsorption, whereas other classes of reduce it
• The inhibition of of the Sodium/chloride cotransporters helps to: low the intercellular of sodium, facilitating the diffusion the calcium ion channels (TRPV5) expressed- on the lumen membrane

Magnesium Reabsorption

• Overall reabsorption of Mg2+ by the nephron is ~95%, leaving ~5% for excretion
• The greatest site magnesium reabsorption occurs at loop of henle’s ascending limb while The rest is reabsorbed mostly in the PCT but also some in in DCT
• Around 20% of plasma Magnesium is bound to proteins
• Not as permeable to magnesium as compared to other electrolytes

Magnesium Reabsorption in PCT

• 30% of the filtered load is reabsorbed
• Water reabsorption along the proximal tubule causes luminal Mg2+ concentration to increase, establishing a favorable electrochemical gradient for passive paracellular Mg2+ reabsorption

Magnesium Reabsorption in Thick Ascending Limb of Loop of Henle

• Major site of Mg2+ reabsorption, 60% is reabsorbed driven by a favorable lumen positive potential difference. Driven by the lumen positive potential difference with ROMK channels

Magnesium reabsorption in distal convoluted tubule

• Around 5% of Mg2+ is reabsorbed
• Mg2 + entry across the apical membrane occurs/via the TRPM6 cation channel
• Mg2 ++ extrusion across the basolateral membrane by secondary active transport by Na-Mg exchange (secondary) active transport

Water Balance

• Body fluid osmolarity is kept about ~290 mOsm/L
• Even slight fluid changes kick off a flurry hormones responses to make-alterations at the water/re-absorption level/ kidneys
• Control is at the level of the later Distal Tubule/CD

Antidiuretic Hormone - Action at Renal Tubule

• Increase/Water permeability/main calls distal tubule CD
• Increase activity cotransporter the thin/ascending enhancing multi/corticopapillary Osm gradient.
• Increase urea (permeability inner medullary CD enhancing area gradient
• ADH binds /V2 receptors/basolateral causing conversion ADP (Stimulatory’s G proteins coupled)
• Camp will ACT protein kinases which activate Intracellular-structures.
• The vesicles will contain " aquaporin 2) are shepharded To the Lumen.

Corticopapillary Osmotic Gradient

• Osmolarity cortex ~ 300 mosm close rest body, fluids.
• As move/cortex to- medulla(inner/outer/papilla ) /Progressively/interstitial. Fluido Osm increases./up/ 1,200 tip
• (Countercurrent/Multiplication/Function loop, deposits NACL in deeper areas kidney/Urea, recycling)
• A(Functions/ Inner medullary CD deposits/Urea.

Countercurrent Multiplication

• Func Loop. Of Henlee Deposits.
• NACL. INTERS FLUID- DEEPER regions/ kidneys build. up’s a gradient osmolarity (through repeating process)
• (SINGLE/EFECT) func 1/ thick. ascending. Limb /NaCl 2-CI
• RECALL (thicker ascending) Impermeable

Urea Transport/Recycling

• In PCT: 50% filtered is /Rear
• IN thin descending limb is /Secreted
• Thick descending. limb/ distil tubule (and parts of the the CD’S) are all "IMP"" too urea’ can concentrate here to 110 %
• IN collectors, ducts = UREA Reabsorb using UT1 (move. down the Concentrate. gradient/ ADH-sensitive
  • Causes (Increased) osmolarity .in THE inner parts The CD." In vasa recta has oxygen & nutrients to to the Medela.

Learn about sodium reabsorption in the proximal convoluted tubule (PCT). The PCT reabsorbs 67% of filtered sodium. Understand early and late PCT processes and the importance of isosmotic reabsorption for maintaining ECF volume.