15 - Salt and Water Balance

water/electrolyte absorption in small intestine

isotonic NaCl absorption

• post-prandial (after meal) → coupled nutrient-Na⁺ absorption

  • SGLT1 (glucose + Na⁺), AA/Na⁺ cotransporters

  • Na⁺ absorbed into cell, Cl^- follows passively paracellularly, water follows osmotically

• between meals

  • Na⁺/H⁺ exchanger (NHE) → brings Na⁺ into cell, secretes H⁺ into lumen

  • Cl^-/HCO₃^- exchanger (DRA) → brings Cl^- into cell, secretes HCO₃^- into lumen

water/electrolyte secretion in small intestine

isotonic NaCl secretion

• Na⁺/2Cl^-/K⁺ transporter → basolateral transporter that provides Cl^- into cell

• CFTR Cl^- channel → secretes Cl^- into lumen

  • activated by cAMP

  • secretin, VIP, and enterotoxins upregulate cAMP

• Na⁺ and water diffuse paracellularly into lumen with Cl^- transport into lumen

cholera

E. coli enterotoxin activates cAMP, stimulating activation of CFTR

• massive Cl^- secretion, with Na⁺ and water secretion

• leads to diarrhea, with very high Cl^- in stool

• causes metabolic acidosis due to loss of HCO₃^-

water/electrolyte absorption in colon

• ENaC → apical Na⁺ channel entry into cell

• NHE → Na⁺/H⁺ exchanger absorbs Na⁺ into cell

• DRA → Cl^-/HCO₃^- exchanger absorbs Cl^- into cell

• SMCT1 → short-chain FA and Na⁺ cotransporter into cell

KHCO₃ secretion in colon

colon has tight junctions, where luminal side becomes very negative from Na⁺ absorption

• K⁺ channels → apical channels push K⁺ out

• DRA → allow HCO₃^- secretion when exchanging Cl^- for absorption

colonic diarrhea

causes hypokalemia and metabolic acidosis due to loss of K⁺ and HCO₃^-

DRA deficiency

DRA (Cl^-/HCO₃^-) brings Cl^- into cell and HCO₃^- out to lumen

• loss of DRA results in inability of absorbing Cl^- and inability to secrete HCO₃^-

• associated with metabolic alkalosis and very high Cl^- in stool

mechanisms of diarrhea

• reduced absorption of water or electrolytes

  • congenital chloride diarrhea (DRA deficiency) → metabolic alkalosis

  • intestinal hypermobility (IBS) → shorten transit tiem

  • anxiety, emotional upset, etc

• enhanced secretion of water and electrolytes

  • activation of cAMP and CFTR

  • E. coli enterotoxin, cholera

  • VIP tumors → stimulate cAMP

calcium absorption

• apical calcium entry:

  • Ca²⁺ channels

  • membrane Ca²⁺-binding protein → brings Ca²⁺ across cell

• inside cell:

  • bind calbindin → binding protein

  • stored in vesicles

• exit pathways:

  • Ca²⁺-ATPase

  • Na⁺/Ca²⁺ exchanger (NCX)

  • exocytosis of vesicles

regulation of Ca²⁺ absorption

vitamin D₃ increases Ca²⁺ uptake, intracellular transport, and export

• low plasma Ca²⁺ stimulates PTH to form vitamin D₃ in kidneys

• upregulates apical Ca²⁺ channels, intracellular calbindin, and Ca²⁺-ATPase in enterocytes

iron absorption

occurs in duodenum and jejunum

• entry into enterocyte:

  • Fe³⁺ (ferric) reduced to Fe²⁺ (ferrous) by iron reductase on membrane

  • DCT1 → Fe²⁺/H⁺ cotransporter into cell

  • heme transporter → transports heme into cell

• inside cell:

  • enzymatic modifications:

    • heme oxidase → converts heme to Fe²⁺

    • ferroxidase → oxidizes Fe²⁺ to Fe³⁺

  • absorption pathway → Fe³⁺ binds iron-binding proteins (mobilferrin)

  • storage pathway → Fe³⁺ binds ferritin irreversibly for storage inside cell

• exit pathway:

  • iron-binding proteins deliver Fe³⁺ to basolateral membrane

  • hephaestin/IREG1 → export Fe³⁺

  • enters plasma bound to transferrin

iron regulatory protein (IRP)

• increases uptake of Fe²⁺ via regulation of DCT1

• increases transportation of Fe³⁺ via upregulation of IREG1

• prevents irreversible trap of Fe³⁺ via downregulation of apoferritin

regulation of iron absorption

• if plasma Fe is low → IRP activity increases

  • crypt stem cells differentiate into enterocytes with high iron absorption capacity

  • takes 3-5 days to appear at villus tip and be functional

• if plasma Fe is high → enterocytes increase ferritin synthesis to trap iron and prevent absorption