Ramesh Ganesan, Reeves W Brian
Division of Nephrology, Pennsylvania State College of Medicine, Hershey 17033, USA.
Am J Physiol Renal Physiol. 2003 Oct;285(4):F610-8. doi: 10.1152/ajprenal.00101.2003. Epub 2003 Jul 15.
Cisplatin produces acute renal failure in humans and mice. Previous studies have shown that cisplatin upregulates the expression of TNF-alpha in mouse kidney and that inhibition of either the release or action of TNF-alpha 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-alpha-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-alpha expression, ICAM-1 expression, and serum TNF-alpha 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-alpha-mediated inflammation in the kidney in response to cisplatin.
顺铂可导致人类和小鼠出现急性肾衰竭。先前的研究表明，顺铂可上调小鼠肾脏中肿瘤坏死因子-α（TNF-α）的表达，并且抑制TNF-α的释放或作用可保护肾脏免受顺铂诱导的肾毒性。在本研究中，我们检测了顺铂对肾脏中TNF受体TNFR1和TNFR2表达的影响，以及每个受体在介导顺铂肾毒性中的作用。向C57BL/6小鼠注射顺铂导致肾脏中TNFR1和TNFR2 mRNA水平上调。在TNF-α缺陷小鼠中，TNFR2而非TNFR1的上调受到抑制，表明TNFR2的上调依赖配体。为了研究每个受体的作用，我们给TNFR1或TNFR2缺陷小鼠施用顺铂。与TNFR1缺陷或野生型小鼠相比，TNFR2缺陷小鼠发生的肾功能障碍较轻，肾脏坏死、凋亡及白细胞浸润减少。此外，与用顺铂处理的野生型或TNFR1缺陷小鼠相比，TNFR2缺陷小鼠的肾脏TNF-α表达、细胞间黏附分子-1（ICAM-1）表达及血清TNF-α水平较低。这些结果表明，TNFR2参与小鼠顺铂诱导的肾损伤，并且可能在顺铂诱导的肾脏TNF-α介导的炎症中起重要作用。
