Cellular differentiation

induced by ischemia can be mimicked by F-actin disassembly mediated by cytochalasin D [11]. Although these correlations are highly suggestive of a central role for actin alterations in the pathophysiology of ischemia-induced surface membrane damage they fall short in providing mechanistic data that directly relate actin cytoskeletal changes to cell injury.

Proximal tubule cell injury during ischemia is also known to be principally responsible for the reduction in GFR. Figure 13-5 illustrates the three known pathophysiologic mechanisms that relate proximal tubule cell injury to a reduction in GFR. Particularly important is the role of the cytoskeleton in mediating these three mechanisms of reduced GFR. First, loss of apical membrane into the lumen and detachment of PTC result in substrate for cast formation. Both events have been related to actin cytoskeletal and integrin polarity alterations [12-15]. Cell detachment and the loss of integrin polarity are felt to play a central role in tubular obstruction (Fig. 13-6). Actin cytoskeletal-mediated tight junction opening during ischemia occurs and results in back-leak of glomerular filtrate into the blood. This results in ineffective glomerular filtration (Fig. 13-7). Finally, abnormal proximal sodium ion reabsorption results in large distal tubule sodium delivery and a reduction in GFR via tubu-loglomerular feedback mechanisms [2,16,17].

In summary, ischemia-induced alterations in proximal tubule cell surface membrane structure and function are in large part responsible for cell and organ dysfunction. Actin cytoskeletal dysregulation during ischemia has been shown to be responsible for much of the surface membrane structural damage.

0 0

Post a comment