Role of calcium in pathogenesis of acute renal failure

Abstract

The potential for calcium to play a key role in cell injury has been long suspected. Major sites of calcium action to promote cell injury include the plasma membrane, mitochondria, endoplasmic reticulum, and the cytoskeleton. Major mechanisms of calcium action to promote cell injury include activation of phospholipases, direct and indirect effects on permeability pathways, and effects on contractile and cytoskeletal structure and function. The activation of phospholipases and deterioration of mitochondrial structure and function by calcium appear to be most important in the evolution of cell injury. Tissue calcium levels invariably increase when lethal cell injury develops in a tissue and is due predominantly to mitochondrial accumulation and sequestration. The simultaneous occurrence of cell calcium overload and lethal cell injury, however, only establishes an association between these two events but does not prove causality. Over the past several years, a large amount of data has established that calcium plays a critical modifying role in the pathogenesis of both ischemic and toxic cell injury, but evidence for the thesis that calcium is the “final common pathway” for lethal cell injury is not conclusive. Many studies have emphasized the role of calcium influx from extracellular to intracellular spaces with resulting cellular calcium overload in cell injury. A critical role for intracellular redistribution of calcium pools rather than cellular calcium influx during the important early stages of cell injury may be more important. Modifying alterations in cell calcium redistribution or cellular calcium influx with a variety of agents has been beneficial in ameliorating the degree of cell injury in a number of experimental settings. It is still unclear whether these beneficial effects are due mainly to alterations of calcium-mediated processes that determine the reversibility of injury or are due to alterations in other critical metabolic processes not importantly influenced by calcium.