Inflammatory signaling pathways, such as mitogen-activated protein kinases, were less activated in renal allografts from hydrogen water-treated rats as compared with regular water-treated rats.75 WF-to-LEW model of CAN Solini et al76 developed a model of CAN using a fully MHC-mismatched rat strain combination, with WF rats as kidney donor and LEW rats as recipients. Several different combinations of inbred and outbred rat combinations have been reported to investigate the multiple aspects of transplantation, including acute rejection, cellular and humoral rejection mechanisms and their treatments, CAN, and potential targets for its prevention. and in this model using three different immunosuppressive regimens. CNQX All animals received cyclosporin 10 mg/kg/day for 10 days, but two further groups were maintained on either cyclosporin 6 mg/kg/day or MMF 20 mg/kg/day. At the end of 8 weeks, CAN was evident in all groups, but the expression of in grafted kidneys was significantly higher in the MMF than in the cyclosporine group, helping to explain the mechanism by which MMF ameliorates transplant arteriosclerosis in experimental chronic rejection. There was no significant difference between the cyclosporin and the MMF groups in the expression of em HO-1, Bcl-2 /em , and em Bcl-XL /em .73 Similar results were observed when rapamycin was compared with tacrolimus in this model.74 Fractalkine is a unique chemokine that functions both as a potent chemoattractant molecule (soluble form)1 and as an adhesion molecule (membrane anchored form) for cells expressing the fractalkine receptor CD197 CX3CR1, such as monocytes, NK (natural killer) cells, and subsets of CD8+ T-cells, involved in chronic transplant arteriosclerosis. Cao et al32 demonstrated increased expression of the fractalkine receptor CX3CR1 in the SD-to-WF model of RT. Fractalkine/CX3CR1 was mostly expressed in the tubulointerstitium and tubular epithelial cell basolateral membrane. A proportion of the CNQX vessel showed positive staining for fractalkine/CX3CR1, occasionally in glomerular parietal wall cells, was significantly lower in MMF than cyclosporine-treated animals.32 LEW-to-BN model of CAN Transplanting kidneys from LEW-to-B (RT1n) rats shows interstitial mononuclear cell infiltration, tubulitis, and glomerulitis, in addition to early phase of arteritis at 30 days. By 80 days, TA is seen in 25%C50% and interstitial fibrosis in up to 25% of renal cortex. There is focal, diffuse, segmental, or globular glomerulosclerosis. In a study by Neto et al,33 all recipients had received tacrolimus (0.5 mg/kg/day) for 7 days. Cardinal et al75 demonstrated that the administration of CNQX molecular hydrogen dissolved in water to this model slowed the progression of CAN, reduced oxidant injury and inflammatory mediator production, and improved overall survival. Inflammatory signaling pathways, such as mitogen-activated protein kinases, were less activated in renal allografts from hydrogen water-treated rats as compared with regular water-treated rats.75 WF-to-LEW model of CAN Solini et al76 developed a model of CAN using a fully MHC-mismatched rat strain combination, with WF rats as kidney donor and LEW rats as recipients. The two strains differ for class I, class II, and non-MHC genes. Cyclosporin (5 mg/kg/day, intramuscularly) needed to be given for the first 10 days to prevent acute rejection. At 120 days, the allografts developed features of CAN and donor-specific antibodies and chronic antibody-mediated rejection.76 A few studies have been carried out in this model, which include gene transfer of CTLA-4 Ig into donor kidney, leading to prevention of progressive proteinuria and CAN, and transfer of donor-specific T helper-2 clones into recipient rats to regulate alloimmune response and prevention of CAN.77,78 Conclusion We reviewed the relevant published literature that described RT in rat models of CAN employing combinations of strains and the outcomes of various interventions. We believe that the review will help researchers to understand the application of various rat models of CAN in understanding the molecular mechanisms and development CNQX of novel treatments for CAN. Footnotes Disclosure The authors report no conflicts of interest in this work..