Abstract 1489: Vitamin D Receptor Activation Modulates the Effect of Uremia on Aortic Gene Expression and Endothelial Function
Vitamin D receptor (VDR) activation therapy is associated with cardiovascular/survival benefit in chronic kidney disease (CKD), but the mechanism of action is not well understood. The aim of this study is to investigate how uremia affects gene expression in aorta and whether VDR activation modulates the uremic effect. DNA microarray technology was used to assess the gene expression profile in aorta prepared from SHAM and 5/6 nephrectomized (NX) rat, a model of Stage 4/5 CKD, treated with or without 0.17 μg/kg paricalcitol, a VDR activator. As expected, paricalcitol at 0.17 μg/kg after two weeks of treatment effectively suppressed serum parathyroid hormone (PTH); no significant difference was observed in ionized calcium or serum phosphorus. Uremia exhibited a significant effect on the gene expression pattern in the aorta, affecting 468 sequences ( ≥1.5-fold changes with p<0.01 vs. SHAM). When the criteria were tightened to ≥ 2-fold changes with p<0.01, uremia still affected 135 target sequences in the rat aorta with 63 up-regulated and 72 down-regulated. Target genes fell into various categories including metabolism and cellular metabolism. Paricalcitol treatment normalized 95 out of the 135 sequences affected by uremia; many of the genes were related to mitochondrial function and oxidative stress. As a follow-up to the microarray analysis, endothelial function was examined. Uremia significantly affected aortic relaxation (−50.0 ± 7.4% in NX rats vs. −96.2 ± 5.3% in SHAM at 30 μM acetylcholine). The endothelial-dependent relaxation response to acetylcholine (Ach) at 30 μM was improved to −58.2 ± 6.0%, −77.5 ± 7.3% and −90.5 ± 4.0% in NX rats treated with paricalcitol at 0.021, 0.042 and 0.083 μg/kg for two weeks, respectively, while blood pressure and heart rate were not changed. PTH suppression alone didn’t improve endothelial function since cinacalcet, a calcimimetic targeting calcium sensing receptor, suppressed PTH without affecting endothelial-dependent vasorelaxation. In conclusion, VDR activation by paricalcitol modulates the effect of uremia on aortic gene expression and endothelial function independent of PTH and blood pressure control, which may be one of the mechanisms responsible for paricalcitol’s cardiovascular benefit in CKD.