title: Different vitamin D receptor agonists exhibit differential effects on endothelial function and aortic gene expression in 5/6 nephrectomized rats.
abstract: Endothelial dysfunction, common in chronic kidney disease (CKD), significantly increases cardiovascular disease risk in CKD patients. This study investigates whether different vitamin D receptor agonists exhibit different effects on endothelial function and on aortic gene expression in an animal CKD model. The 5/6 nephrectomized (NX) rat was treated with or without alfacalcidol (0.02, 0.04 and 0.08μg/kg), paricalcitol (0.04 and 0.08μg/kg), or VS-105 (0.004, 0.01 and 0.16μg/kg). All three compounds at the test doses suppressed serum parathyroid hormone effectively. Alfacalcidol at 0.08μg/kg raised serum calcium significantly. Endothelial function was assessed by pre-contracting thoracic aortic rings with phenylephrine, followed by treatment with acetylcholine or sodium nitroprusside. Uremia significantly affected endothelial-dependent aortic relaxation, which was improved by all three compounds in a dose-dependent manner with alfacalcidol and paricalcitol exhibiting a lesser effect. DNA microarray analysis of aorta samples revealed that uremia impacted the expression of numerous aortic genes, many of which were normalized by the vitamin D analogs. Real-time RT-PCR analysis confirmed that selected genes such as Abra, Apoa4, Fabp2, Hsd17b2, and Hspa1b affected by uremia were normalized by the vitamin D analogs with alfacalcidol exhibiting less of an effect. These results demonstrate that different vitamin D analogs exhibit different effects on endothelial function and aortic gene expression in 5/6 NX rats. This article is part of a Special Issue entitled '17th Vitamin D Workshop'.
authors.affiliation: Vidasym, Chicago, IL, United States. Electronic address: ruth.wuwong@prodigy.net.
authors.forename: J Ruth
authors.initials: JR
authors.lastname: Wu-Wong
authors.affiliation: Department of Pathology & Laboratory Medicine, University of California, Los Angeles, CA, United States.
authors.forename: Xinmin
authors.initials: X
authors.lastname: Li
authors.affiliation: Vidasym, Chicago, IL, United States.
authors.forename: Yung-Wu
authors.initials: YW
authors.lastname: Chen
mesh_terms: D000818:Animals; D001011:Aorta / Q000187:drug effects* / Q000378:metabolism; D002117:Calcitriol / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000601:surgery; D009392:Nephrectomy; D051381:Rats; D018167:Receptors, Calcitriol / Q000819:agonists*; D014815:Vitamins / Q000494:pharmacology*
chemical_list: D018167:Receptors, Calcitriol; D014815:Vitamins; D002117:Calcitriol
keywords: Alfacalcidol; Aortic gene expression; Endothelial function; Kidney disease; Paricalcitol; VS-105; Vitamin D analogs; Vitamin D receptor