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TNFR2-mediated apoptosis and necrosis in cisplatin-induced acute renal failure

Division of Nephrology, The Pennsylvania State College of Medicine, Hershey 17033, and Lebanon Veterans Affairs Medical Center, Lebanon, Pennsylvania 17042

Submitted 12 March 2003 ; accepted in final form 9 June 2003

Cisplatin produces acute renal failure in humans and mice. Previous studies have shown that cisplatin upregulates the expression of TNF- in mouse kidney and that inhibition of either the release or action of TNF- protects the kidney from cisplatin-induced nephrotoxicity. In this study, we examined the effect of cisplatin on the expression of TNF receptors TNFR1 and TNFR2 in the kidney and the role of each receptor in mediating cisplatin nephrotoxicity. Injection of cisplatin into C57BL/6 mice led to an upregulation of TNFR1 and TNFR2 mRNA levels in the kidney. The upregulation of TNFR2 but not TNFR1 was blunted in TNF--deficient mice, indicating ligand-dependent upregulation of TNFR2. To study the roles of each receptor, we administered cisplatin to TNFR1- or TNFR2-deficient mice. TNFR2-deficient mice developed less severe renal dysfunction and showed reduced necrosis and apoptosis and leukocyte infiltration into the kidney compared with either TNFR1-deficient or wild-type mice. Moreover, renal TNF- expression, ICAM-1 expression, and serum TNF- levels were lower in TNFR2-deficient mice compared with wild-type or TNFR1-deficient mice treated with cisplatin. These results indicate that TNFR2 participates in cisplatin-induced renal injury in mice and may play an important role in TNF--mediated inflammation in the kidney in response to cisplatin.

acute tubular necrosis; gene expression; tumor necrosis factor; tumor necrosis factor receptor; cytokines

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