Tumor Necrosis Factor-α Induces Intrinsic Apoptotic Signaling During Renal Obstruction Through Truncated Bid Activation

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Abstract

Purpose:

Tumor necrosis factor-α has a significant role in renal tubular cell apoptosis during obstruction induced renal injury. While we have previously reported the role of tumor necrosis factor-α in extrinsic pathway apoptotic signaling during renal obstruction, to our knowledge its effect on intrinsic pathway signaling and mitochondrial release of cytochrome C has not previously been evaluated.

Materials and Methods:

Male Sprague-Dawley rats were anesthetized and underwent unilateral ureteral obstruction vs sham operation. At 24 hours before surgery and every 84 hours thereafter the animals received vehicle or a pegylated form of soluble tumor necrosis factor receptor type 1. The kidneys were harvested 1 week postoperatively. The renal cortex was analyzed for tumor necrosis factor-α production (enzyme-linked immunosorbent assay), apoptosis (TUNEL and enzyme-linked immunosorbent assay), Bcl-2, Bcl-xL, Bax, caspase 8 and truncated Bid expression (Western blot), and mitochondrial cytochrome C release (immunohistochemistry).

Results:

Renal obstruction induced increased tumor necrosis factor-α production, apoptotic renal tubular death, the expression of Bax, caspase 8 and truncated BID, and mitochondrial release of cytochrome C, while simultaneously stimulating decreased Bcl-2 and Bcl-xL expression. Treatment with the pegylated form of soluble tumor necrosis factor receptor type 1 significantly decreased obstruction induced tumor necrosis factor-α production, apoptosis, Bax, caspase 8, truncated Bid expression and mitochondrial cytochrome C release, and increased Bcl-2 and Bcl-xL expression.

Conclusions:

These results demonstrate that tumor necrosis factor-α stimulates Bid and subsequent intrinsic apoptotic signaling pathway activation during unilateral ureteral obstruction, resulting in mitochondrial cytochrome C release and apoptotic cell death. We identified tumor necrosis factor-α neutralization as a potential therapeutic option for ameliorating obstruction induced renal injury.

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