Pyrrolidine-dithio-carbamate Ammonium (PDTC)counteracts High-phosphate-induced Vascular Calcification In Uremic Rat

Objective:Cardiovascular disease (CVD) is the leading cause of death in patients with end-stage renal disease (ESRD). The CVD incidence is as high as50%,20-30times higher than that in the general population. Vascular calcification (VC) is an independent risk factors associated with CVD and mortality in ESRD patients. VC has been associated with traditional cardiovascular risk factors, such as old age, hypertension, dyslipidemia, diabetes and smoking, as well as with non-traditional cardiovascular risk factors, including hyperphosphatemia, oxidative stress, and inflammatory fctors. Recent studies indicated that the etiology of VC is multifactorial and is induced by various comlex mechanism. Nuclear factor NF-κB palys an important role in regulating inflammatory responses, which augments the expression of various inflammatory factors. Recently several studies revealed that the NF-κB plays a role in VC induced by oxidative stress and inflammatory reactions. pyrrdidine-dithio-carbamate ammonium (PDTC), an efficent NF-κB inhibitor, inhibits the activation of NF-κB and accordingly interdicts the biological effects caused by the NF-κB pathway. The aim of the present study was to investigate the effects of PDTC on high-phosphate-induced VC in uremic rats.Methods:Twenty-four eight-week-old Sprague-Dawley rats were randomly divided into3groups. The animals in control group (n=8) were fed with standard chow containing1.2%calcium and0.6%phosphorus. The uremic rats in CRF group (n=8) and PDTC group (n=8) were fed with diet containing0.75%adenine,1.2%calcium, and1%phosphorus for8weeks, and the animals in PDTC group were administrated PDTC intraperitoneally,(100mg/kg/d) The abdominal aortas were excised for pathological evaluation, and determinated the expression of NF-κB p65, osteopontin (OPN) and core binding factor α1(Cbfα-1) protein by western blot and immunostaining assays.Results:At the end of4weeks and8weeks (P<0.01), serum creatinine, inorganic phosphate, calcium-phosphorus product increased significantly in CRF group and PDTC group compared with those in control group, although no differences were found between the former two groups. Aortic calcification was found at the end of8 weeks in CRF group and PDTC group, and western blot showed that total NF-κB p65, nuclear phosphorylated-p65(p-p65), OPN and cbfal expressions in the former group were significantly higher than those in the latter group (P<0.01). The immunostaining assay revealed that the changes of OPN and cbfal expression were similar to the results of western blot assays. The expression of Cbfa-1was positively correlated with NF-kB p65and nuclear phosphorylated-p65(p-p65)(r=0.707, P=0.000; r=0.507, P=0.000).Conclusion:NF-κB signaling pathways is activated in aortic calcification in CRF rats, and PDTC significantly inhibites partially p65nuclear translocation and high-phosphorus-induced aortic calcification.