Vitamin D Receptor Activation Mitigates the Impact of Uremia on Endothelial Function in the 5/6 Nephrectomized Rats

J Ruth Wu-Wong,Kristin A Brooks,Bryan Cox,James S Polakowski,Masaki Nakane,William Noonan,Jason A Segreti

doi:10.1155/2010/625852

Abstract

Endothelial dysfunction increases cardiovascular disease risk in chronic kidney disease (CKD). This study investigates whether VDR activation affects endothelial function in CKD. The 5/6 nephrectomized (NX) rats with experimental chronic renal insufficiency were treated with or without paricalcitol, a VDR activator. Thoracic aortic rings were precontracted with phenylephrine and then treated with acetylcholine or sodium nitroprusside. Uremia significantly affected aortic relaxation (−50.0 ± 7.4% in NX rats versus −96.2 ± 5.3% in SHAM at 30 μM acetylcholine). The endothelial-dependent relaxation 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 paricalcitol at 0.042 μg/kg did not affect blood pressure and heart rate. Parathyroid hormone (PTH) suppression alone did not improve endothelial function since cinacalcet suppressed PTH without affecting endothelial-dependent vasorelaxation. N-omega-nitro-L-arginine methyl ester completely abolished the effect of paricalcitol on improving endothelial function. These results demonstrate that VDR activation improves endothelial function in CKD.

Highlights

Chronic kidney disease (CKD) patients experience a high mortality rate from cardiovascular (CV) diseases [1, 2]
We examined the effect of uremia and paricalcitol treatment on acetylcholine-induced endothelial-dependent relaxation of aortic rings from SHAM and 5/6 NX rats
It has been shown that, in spontaneously hypertensive rats (SHR) with impaired endothelial function, oral cholecalciferol treatment significantly improved the endothelium-dependent vascular relaxation and hyperpolarization induced by acetylcholine [26]

Summary

Introduction

Chronic kidney disease (CKD) patients experience a high mortality rate from cardiovascular (CV) diseases [1, 2]. Endothelial dysfunction is commonly observed in CKD, likely preceding other cardiovascular complications [7]. Do changes in renal endothelial function affect the progression of renal disease, and systemic endothelial dysfunction significantly contributes to the severity of cardiovascular complications in CKD. CKD patients usually have hypertension [8] and/or diabetes [9], two of the conventional cardiovascular risk factors that are associated with endothelial dysfunction. Likely other renal specific mechanisms may contribute to endothelial dysfunction in CKD. In early CKD one of the first serum parameters to be altered is a decrease in the serum 1,25-dihydroxyvitamin D3 levels [10], which raises the question of whether deficient VDR activation may be one of the renal specific risk factors for endothelial dysfunction in CKD. Preclinical studies show that VDR may be involved in modulating smooth muscle cell proliferation/differentiation, the renin-angiotensin system, inflammation, thrombosis, and fibrinolysis; many of these factors are involved in endothelial function [11, 12]

Methods

Results

Conclusion