The TNF-α serum level increases after rhabdomyolysis and is involved in the subsequent cardiorenal injury. In the present study， we investigated the TNF-α-dependent cell signaling pathways implicated in cellular injury in these organs. Rhabdomyolysis was induced by intramuscular glycerol injection in rats. Renal function， cardiac and renal pathology， and activation of caspases were evaluated during the first 24 h after glycerol injection. TNF-α blockade with infliximab reduced tubular necrosis and cardiorenal apoptosis. Cellular Fas-associated protein with death domain-like IL-1β-converting enzyme inhibitory protein (cFLIP)， an inhibitor of caspase-8， was overexpressed in the kidney but not in the... More
The TNF-α serum level increases after rhabdomyolysis and is involved in the subsequent cardiorenal injury. In the present study， we investigated the TNF-α-dependent cell signaling pathways implicated in cellular injury in these organs. Rhabdomyolysis was induced by intramuscular glycerol injection in rats. Renal function， cardiac and renal pathology， and activation of caspases were evaluated during the first 24 h after glycerol injection. TNF-α blockade with infliximab reduced tubular necrosis and cardiorenal apoptosis. Cellular Fas-associated protein with death domain-like IL-1β-converting enzyme inhibitory protein (cFLIP)， an inhibitor of caspase-8， was overexpressed in the kidney but not in the heart. The inhibitory effect of cFLIP blunted caspase-8 activation in the kidney. In this condition， the cellular response to the TNF-α stimulus was driven to receptor-interacting protein-1 (RIP1)-mediated necroptosis. Treatment with RIP1 inhibitor (necrostatin-1) isolated or in combination with infliximab showed a similar reduction in tubular necrosis， underscoring the importance of TNF-α-mediated tubular necroptosis in this model. TNF-α played a positive regulatory role in the transcription of proapoptotic Bax and p53-upregulated modulator of apoptosis (PUMA) proteins. Infliximab treatment reduced caspase-9-mediated apoptosis in both organs. Treatment with a caspase-8 inhibitor showed that caspase-8 participated in the process of apoptosis only in the heart， upstream of caspase-9 activation. TNF-α-mediated necroptosis is the predominant form of tubular injury observed in the glycerol model. TNF-α up regulates Bax and PUMA proapoptotic proteins， resulting in activation of the intrinsic pathway of apoptosis in the kidney and heart.
