Cephaloridine (CER), a cephalosporin antibiotic, has been proven to be nephrotoxic, and has been reported to induce acute renal failure as a side effect in both experimental animals and humans. 1-3) Experimental animals injected with CER undergo renal damage characterized by acute proximal tubular necrosis, most prominently of the S2 segment of the tubules, 4) where CER is transported by the renal basolateral transport system for organic anions from the blood to the proximal tubular cells. 5)

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... wever, CER is limited in its movement to the tubular lumen, resulting in its high accumulation within the proximal tubular cells, which are critical for promoting the development and progression of renal disease. [6] [7] [8] Serum thymic factor (FTS) is a nonapeptide thymic hormone which was first isolated from pig serum by Bach et al. and then from the thymus. 9) FTS is secreted by thymic epithelial cells and is involved in functional activation and differentiation in T cells. 10, 11) In addition to its action as a thymic hormone, FTS exerts a variety of biological activities both in vivo and in vitro, including an immunobiological effect. 12-15) Previous reports have shown that FTS prevents experimental pancreatitis and diabetes induced by alloxan or streptozotocin, and diabetes and myocarditis caused by the encephalomyocarditis virus in mice. 16, 17) Other studies have reported that FTS also suppresses acute experimental allergic encephalomyelitis and skin fibrosis during wound repair. 18, 19) CER nephrotoxicity is due in part to the generation of reactive oxygen species (ROS), and the ROS-induced peroxidation of cell membrane lipids is the most likely mechanism of renal injury caused by CER. [20] [21] [22] [23] Recently, ROS have been demonstrated to modulate signaling pathways in cellular responses. 24) The mitogen-activated protein kinase (MAPK) family are important mediators of signal transduction processes that serve to coordinate cellular responses to a variety of extracellular stimuli. Mammals express at least four distinctly regulated groups of MAPKs, the extracellular signal-regulated protein kinase (ERK) 1/2, c-Jun N-terminal kinase (JNK), p38 MAP kinase and ERK5 cascades are each capable of responding to different stimuli, such as cellular stress and growth factors. 25) The most well characterized of these is the ERK pathway. Numerous studies have demonstrated that the ERK pathway is mainly activated by a variety of growth factors and known to be associated with cellular proliferation and differentiation. 26, 27) Several in vivo studies have shown that the ERK cascade is phosphorylated in the damaged brain caused by ischemia and hypoglycemia. 28, 29) The biological outcome of MAPK activation may be attributed to difference in cell types. We and others have previously demonstrated that ROS mediate CER-induced renal damage. [20] [21] [22] [23] 30, 31) A previous report has shown that FTS increases superoxide disumutase (SOD) levels in senescence-accelerated mice. 32) It has also been reported that bleomycin-induced pulmonary injury can be prevented by the administration of FTS. 33) Thus, we hypothesize that FTS, having a variety of biological activities, might modify cell damage and tissue injury, and possibly attenuate free radical-mediated renal cell injury and nephrotoxicity caused by CER. We have previously reported that an MEK/ERK pathway is probably concerned in free radical-induced injury in rat renal cortical slices. 34) In the present study, we investigated our hypothesis whether FTS prevents the development of CER-induced nephrotoxicity in vivo and in vitro. The aim of this study was also to examine the effect of FTS on CER-induced ERK activation in the rat kidney. Serum thymic factor (FTS), a thymic peptide hormone, has been reported to increase superoxide disumutase (SOD) levels in senescence-accelerated mice. In the present study, we examined the effect of FTS on cephaloridine (CER)-induced nephrotoxicity in vivo and in vitro. We previously reported that CER led to extracellular signal-regulated protein kinase (ERK) activation in the rat kidney. So, we also investigated whether FTS has an effect on ERK activation induced by CER. Treatment of male Sprague-Dawley rats with intravenous CER (1.2 g/kg) for 24 h markedly increased BUN and plasma creatinine levels and urinary excretion of glucose and protein, decreased creatinine clearance and also led to marked pathological changes in the proximal tubules, as revealed by electron micrographs. An increase in phosphorylated ERK (pERK) was detected in the nuclear fraction prepared from the rat kidney cortex 24 h after CER injection. Pretreatment of rats with FTS (50 m mg/kg, i.v.) attenuated the CER-induced renal dysfunction and pathological damage. FTS also suppressed CER-induced ERK activation in the kidney. In vitro treatment of the established cell line, LLC-PK 1 cells, with FTS significantly ameliorated CER-induced cell injury, as measured by lactate dehydrogenase (LDH) leakage. Our results, taken together with our previous report that MEK inhibitors ameliorated CER-induced renal cell injury and ERK activation induced by CER, suggest that FTS participates in protection from CER-induced nephrotoxicity by suppressing ERK activation induced by CER.