STUDIES OF RENAL INJURY .2. ACTIVATION OF THE GLUCOSE-TRANSPORTER-1 (GLUT1) GENE AND GLYCOLYSIS IN LLC-PK1 CELLS UNDER CA2+ STRESS

Injury to the renal proximal tubule is common and may be followed by e ither recovery or cell death. The survival of injured cells is support ed by a transient change in cellular metabolism that maintains life ev en when oxygen tension is reduced. This adaptive process involves the activation of the gene encoding the glucose transporter GLUT1, which i s essential to maintain the high rates of glucose influx demanded by g lycolysis. We hypothesized that after cell injury increases of cell Ca 2+ (Ca-i(2+)) initiate the flow of information that culminates with th e upregulation of the stress response gene GLUT1. We found that elevat ions of Ca-i(2+) caused by the calcium ionophore A23187 activated the expression of the GLUT1 gene in LLC-PKI cells. The stimulatory effect of Ca-i(2+) on GLUT1 gene expression was, at least in part, transcript ional and resulted in higher levels of GLUT1 mRNA, cognate protein, ce llular hexose transport activity, glucose consumption, and lactate pro duction. This response was vital to the renal cells, as its interrupti on severely increased Ca2+-induced cytotoxicity and cell mortality. We propose that increases of Ca-i(2+) initiate stress responses, represe nted in part by activation of the GLUT1 gene, and that disruption to t he flow of information originating from Ca2+-induced stress, or to the coordinated expression of the stress response, prevents cell recovery after injury and may be an important cause of permanent renal cell in jury and cell death.