MP59-01 NOVEL NUCLEAR FACTOR-κB ACTIVATION INHIBITOR, DEHYDROXYMETHYLEPOXYQUINOMICIN, PREVENTS THE DEVELOPMENT OF CHRONIC CYCLOSPORINE NEPHROPATHY

Abstract

INTRODUCTION AND OBJECTIVE: The nephrotoxicity of the calcineurin inhibitors including cyclosporine is a major problem in the kidney transplantation. We investigated the effect of a novel nuclear factor-κB (NF-κB) activation inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ), on chronic cyclosporine nephropathy using a rat model. METHODS: We performed 5/6 nephrectomy in Sprague-Dawley rats bred with low sodium diet. These rats were treated with the intraperitoneal administration of relatively high doses of cyclosporine (15mg/kg daily) (cyclosporine group, N=6) or treated with 5% glucose solution (control group, N=6). The other group was additionally treated with the intraperitoneal administration of DHMEQ (8mg/kg daily) (DHMEQ treatment group, N=6). Urine samples were collected on day 28 for 24 hours. The blood was collected and the kidneys were harvested on day 29. The sections of the kidney samples with Masson-trichrome staining were scanned and the area of interstitial fibrosis was measured by using a software (Image J). The proteins in the cytoplasm and the nucleus were separately collected from the samples to measure the relative increase in NF-κB p65 translocation into the nucleus using an enzyme-linked immunosorbent assay (ELISA). RESULTS: The creatinine clearance levels in the DHMEQ treatment group were significantly higher in comparison with the cyclosporine group (0.74 ± 0.11 ml/min vs. 0.55 ± 0.05 ml/min, respectively). The Area measurements demonstrated that the interstitial fibrosis in the renal cortex less developed in the DHMEQ treatment group than those in the cyclosporine group (13.4 ± 7.0 % vs. 35.5 ± 18.3 %, respectively). The ELISA assays showed that the relative ratio of nuclear to cytoplasmic p65 in kidney samples in the cyclosporine group was up-regulated in comparison with that in the control group (4.33 ± 2.06 vs. 0.83 ± 0.26, respectively), while that in the DHMEQ treatment group was down-regulated in comparison with the cyclosporine group (1.34 ± 0.55 vs. 4.33 ± 2.06, respectively). CONCLUSIONS: Treatment with DHMEQ prevents the development of renal interstitial fibrosis due to chronic cyclosporine nephropathy and maintains the renal function. Source of Funding: None