POLARITY, INTEGRIN, AND EXTRACELLULAR-MATRIX DYNAMICS IN THE POSTISCHEMIC RAT-KIDNEY

Acute renal failure (ARF) as a consequence of ischemic injury is a com mon disease affecting 5% of the hospitalized population. Despite the f act that mortality from ARF is high, there has been Little improvement in survival rates over the last 40 years. The pathogenesis of ARF may be related to substantial changes in cell-cell and cell-extracellular matrix interactions mediated by beta(1)-integrins. On the basis of in vitro and in vivo studies, reorganization of beta(1)-integrins from b asal to apical surfaces of injured tubular epithelia has been suggeste d to facilitate epithelial detachment, contributing to tubular obstruc tion and backleak of glomerular filtrate. In this study, we examine in tegrin and extracellular matrix dynamics during epithelial injury and repair using an in vivo rat model of unilateral ischemia. We find that , soon after reperfusion, beta(1)-integrins newly appear on lateral bo rders in epithelial cells of the S3 segment but are not on the apical surface. At later times, as further injury and regeneration coordinate ly occur, epithelia adherent to the basement membrane localize beta(1) predominantly to basal surfaces even while the polarity of other mark er proteins is lost. At the same time, amorphous material consisting o f depolarized exfoliated cells fills the luminal space. Notably, beta( 1)-integrins are not detected on exfoliated cells. A novel finding is the presence of fibronectin, a glycoprotein of plasma and the renal in terstitium, in tubular spaces of the distal nephron and to a lesser ex tent S3 segments. These results indicate that beta(1)-integrins dramat ically change their distribution during ischemic injury and epithelial repair, possibly contributing to cell exfoliation initially and to ep ithelial regeneration at later stages. Together with the appearance of large amounts of fibronectin in tubular lumens, these alterations may play a significant role in the pathophysiology of ARF.