Abstract 17948: Endothelial Cell Infusion Improves Chronic Kidney Disease-induced Endothelial Dysfunction in 5/6 Nephrectomized Rats
Introduction: Chronic kidney disease (CKD) increases risk of cardiovascular disease (CVD). Endothelial dysfunction, an early step in development of CVD, is prevalent in CKD. This study tested the hypothesis that transfusion of rat aortic endothelial cells (EC), via increasing nitric oxide synthase (NOS) activity, improves vascular reactivity in a rat model of CKD.
Methods and Results: Male Sprague-Dawley rats (11 wk) underwent sham surgery (S) or 5/6 nephrectomy (Nx). Six wks after Nx, EC (1.5 x 106 cells/rat) or vehicle (Nx+Veh) were transfused intravenously. One wk later, vascular reactivity of mesenteric artery was assessed on a wire myograph. Sensitivity of endothelium-dependent relaxation to acetylcholine (ACh) and maximum vasodilation (Emax to 10 μ M ACh) were impaired by Nx and improved by EC transfusion (Fig A, B). Emax was negatively correlated with serum creatinine (r= -0.55, p<0.05). Non-selective inhibition of all NOS activity (LNIO + indomethacin + ODQ) eliminated the effects of Nx and EC transfusion on Emax, indicating that these effects were mediated by NOS. Using selective NOS inhibitors (LNIO for eNOS, LNPA for nNOS, and 1400W for iNOS) we demonstrated that Nx impaired, and EC transfusion improved, activity of eNOS and nNOS (Fig C, D). Plasma ADMA (natural inhibitor of eNOS) was significantly increased by Nx and decreased by EC transfusion (0.18±0.02 [S], 0.32±0.05 [Nx+Veh], 0.12±0.01 [Nx+EC] μ M, p<0.05). mRNA expression of DDAH (enzyme that degrades ADMA) was significantly decreased by Nx and restored by EC transfusion (1.0±0.11 [S], 0.63±0.05 [Nx+Veh], 1.21±0.12 [Nx+EC], p<0.05). Emax was positively correlated with DDAH mRNA expression (r=0.59, p<0.05).
Conclusion: EC transfusion attenuates CKD-induced endothelium-dependent vascular dysfunction by regulating DDAH expression and enhancing eNOS and nNOS activities. These results suggest that EC-based therapy could provide a novel therapeutic strategy to improve vascular function in CKD.
- © 2012 by American Heart Association, Inc.