Molecular mechanisms of liver preconditioning

Figure 2 Na⁺-dependent mechanisms involved in hepatocyte damage by hypoxia and their modulation by ischemic preconditioning. Hypoxia-induced adenosine triphosphate (ATP) depletion causes intracellular acidification, leading to inhibition of Na⁺/K⁺ ATPase and the activation of acid buffering systems (Na⁺/H⁺ exchanger). This leads to an increase in intracellular Na⁺ that precipitates irreversible hepatocyte damage. ATP-dependent signalling through purinergic P2Y receptors prevents Na⁺ accumulation by inhibiting the ERK 1/2-dependent activation of the Na⁺/H⁺ exchanger. Adenosine and nitric oxide (NO) activate the vacuolar proton ATPase that maintains intracellular pH avoiding activation of the Na⁺/H⁺ exchanger. Adenosine also induces the hypoxia-inducible factor 1 (HIF-1) target gene, carbonic anhydrase IX (CAIX), which converts CO₂ into bicarbonate, that once transported into the hepatocytes through the Cl^-/HCO₃^- exchanger, neutralizes the intracellular pH and prevents Na⁺ accumulation. See text and Refs[20,21,25,27,28,43,52,53,58]. P38 MAPK: p38 MAP kinase; PI3-kinase: Phosphatidylinositol 3-kinase; PKC: Protein kinase C.