Pathophysiology and functional significance of apical membrane disruption during ischemia

The characteristic structure of polarized proximal tubule cells is drastica lly altered by the onset of ischemic acute renal failure. Distinctive apica l brush border microvilli disruption occurs rapidly and in a duration-depen dent fashion, Microvillar membranes internalize into the cytosol of the cel l or are shed into the lumen as blebs. The microvillar actin core disassemb les concurrent with or preceding these membrane changes. Actin and its asso ciated binding proteins no longer interact to form these highly regulated a pical membrane structures necessary for microvilli. The resultant epithelia l cells have a reduced apical membrane surface that is not polarized either structurally, biochemically or physiologically. Furthermore, the changes i n the apical microvilli result in tubular obstruction, reduced Na+ absorpti on, and partly explain the reduction in glomerular filtration rate. Recent evidence suggests these actin surface membrane alterations induced by ische mia are secondary to activation and relocation of the actin-associated prot ein, actin depolymerizing factor/cofilin, to the apical membrane domain. Ac tivated (dephosphorylated) actin depolymerizing factor/cofilin proteins bin d filamentous actin, increasing subunit treadmilling rates and filament sev ering. Once activated, the diffuse cytoplasmic distribution of the actin de polymerizing factor/cofilin protein relocalizes to the luminal membrane ble bs. During recovery the actin depolymerizing factor/cofilin proteins are ag ain phosphorylated and reassume their normal diffuse cytoplasmic localizati on. This evidence strongly supports the hypothesis that actin depolymerizin g factor/cofilin proteins play a significant role in ischemia-induced injur y in the proximal tubule cells. Curr Opin Nephrol Hypertens 8:449-458. (C) 1999 Lippincott Williams & Wilkins.