TNF-α-mediated cardio-renal injury after rhabdomyolysis in rats.

In this study, we investigated TNF-α-dependent cell signaling pathways implicated in the cellular injury in these organs. Rhabdomyolysis was induced by intramuscular glycerol injection in rats. The renal function, cardiac and renal pathology and activation of the caspases were evaluated during the first 24 hours after glycerol injection. TNF-α blockade with infliximab reduced the tubular necrosis and cardio-renal apoptosis. 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, cellular response to TNF-α stimulus was driven to RIP1-mediated necroptosis. The treatment with RIP1 inhibitor (necrostatin-1) isolated or in combination with infliximab showed similar reduction in the tubular necrosis, underscoring the importance TNF-α-mediated tubular necroptosis in this model. TNF-α played a positive regulatory role in the transcription of the pro-apoptotic Bax and PUMA proteins. Infliximab treatment reduced the 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 to 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 pro-apoptotic proteins resulting in activation of the intrinsic pathway of apopt...
Source: Am J Physiol Renal P... - Category: Urology & Nephrology Authors: Tags: Am J Physiol Renal Physiol Source Type: research

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PMID: 31792600 [PubMed - as supplied by publisher]
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