Calcium handling by renal tubules during oxygen deprivation injury to the kidney prior to reoxygenation

Summary

Efforts to more precisely define the mechanism(s) of ischemic injury to renal epithelial tissue, both during O₂ deprivation and reflow, have led to the expanding use of freshly isolated renal tubules. This tissue is prepared in a manner that eliminates the impact of changes in vascular resistance and influences of hormones, as well as temporal changes in pH and in regional pO₂, and has permitted investigators to focus on the definitive cellular responses to O₂ deprivation itself. When such studies are evaluated it becomes clear that in vitro anoxia, for up to 60 minutes, is not associated with any increase in total tissue Ca²⁺ as measured by atomic absorption techniques, whereas severe hypoxia is attended by a time-dependent increase in total tissue Ca²⁺. In both severe hypoxia and anoxia, however, the Ca²⁺ uptake rate is increased, but during hypoxia the less severe acidosis, as well as the continued, albeit modest, mitochondrial energization, appears to facilitate mitochondrial (and thus total tissue) Ca²⁺ accumulation. In vivo and in vitro, the administration of calcium channel blockers (CCB) attenuates renal oxygen-deprivation-induced injury and one, often overlooked, effect of verapamil, a prototypical CCB, is to reduce K⁺ loss from treated tissue via inhibition of Ca²⁺-mediated K⁺ efflux pathways. This may be the cause of the higher levels of K⁺ reported for several tisisues, including kidney tubules, during CCB treatment. In addition, reduced rates of Ca²⁺ uptake effected by CCB may modify cytosolic free Ca²⁺ levels such that activation of phospholipases is impaired. Although this interrelationship has not yet been documented, the reduced level of membrane injury, assessed by lower LDH release in CCB-treated tubules, is consistent with such a protective effect. Finally, cellular adenosine triphosphate levels and tissue K⁺ levels recover toward normal more quickly during reoxygenation of verapamil-treated O₂-deprived tubules. These observations, taken together, strongly suggest that direct cellular protection to renal tubules does attend verapamil administration during O₂ deprivation, and the mechanism may involve the prevention of several pathophysiologic events that normally accompany increased Ca²⁺ uptake rate, rather than simply the prevention of tissue Ca²⁺ overload, an event that occurs only in hypoxia, not anoxia.