Mechanisms of cell injury in ATP-depleted proximal tubules. Role of glycine, calcium, and polyphosphoinositides.
Increase of intracellular free Ca2+ (Caf) plays an important role in the deterioration of cell structure that occurs during depletion of adenosine triphosphate (ATP). On the other hand a form of Ca2+ independent cell injury due to glycine deficiency has also been recognized. Normally high intracellular gradients of glycine are dissipated during ATP depletion. Under these circumstances exogenous glycine protects cells and preserves structure independently of metabolism. We have examined the specific contributions of calcium and glycine to the injury process in isolated rabbit proximal tubules depleted of ATP by exposure to a metabolic inhibitor, or additionally made permeable to calcium ions by an ionophore. Tubules were incubated in high or low Ca2+ media (1.25 mM or 100 nM Ca2+) to attain high concentrations of Caf or 'clamp' Caf in the physiological range. Our results showed that structural breakdown in proximal tubule cells is compartmentalized. Increase of Caf leads to specific patterns of membrane damage and phospholipid hydrolysis. On the other hand glycine deficiency leads to a unique membrane defect that occurs independently of phospholipid breakdown and is fully expressed even if calcium-mediated injury is prevented by low Ca2+ conditions. Furthermore, the specificity of glycine was emphasized by its ability to maintain membrane continuity and thus dramatically delay lethal injury in spite of severe structural damage caused by massive increases of Caf.
Venkatachalam
M A
MA
Department of Pathology, University of Texas Health Science Center at San Antonio 78284-7750.
Weinberg
J M
JM
D000255:Adenosine Triphosphate / Q000378:metabolism*; D000596:Amino Acids / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism / Q000494:pharmacology; D005998:Glycine / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000293:injuries / Q000378:metabolism*; D018129:Phosphatidylinositol Phosphates / Q000494:pharmacology; D018009:Receptors, Glycine / Q000378:metabolism
D000596:Amino Acids; D018129:Phosphatidylinositol Phosphates; D018009:Receptors, Glycine; D000255:Adenosine Triphosphate; D002118:Calcium; D005998:Glycine