title: The Effects of Olmesartan and Alfacalcidol on Renoprotection and klotho Gene Expression in 5/6 Nephrectomized Spontaneously Hypertensive Rats.
abstract: Recently, an angiotensin inhibitor has been shown to upregulate the klotho mRNA level in chronic renal failure. In addition, the administration of vitamin D has been reported to improve the mortality of patients with chronic renal failure. In this study, we examined the effects of an angiotensin inhibitor and/or vitamin D on the progression of chronic renal failure by using male 5/6 nephrectomized (5/6Nx) spontaneously hypertensive rats. Male 5/6Nx spontaneously hypertensive rats were assigned to 4 groups as follows: 5/6Nx group, 5/6Nx rats; Alf group, 5/6Nx rats administered alfacalcidol (0.2 μg/kg/day); Olm group, 5/6Nx rats administered olmesartan (15 mg/kg/day); Alf + Olm group, 5/6Nx rats administered alfacalcidol (0.2 μg/kg/day) and olmesartan (15 mg/kg/day). These drugs were administered for 12 weeks. Systolic blood pressure in the Alf, Olm and Alf + Olm groups were significantly decreased relative to that in the 5/6Nx group during the 12-week experimental period. As a result, all treated groups showed renoprotection based on improvement of the systolic blood pressure, urinary protein excretion and histological renal fibrosis. Combination therapy of alfacalcidol and olmesartan was more effective than either alfacalcidol or olmesartan alone. Expression of klotho mRNA was significantly upregulated in the Alf + Olm group in comparison with in the 5/6Nx group. Serum levels of fibroblast growth factor 23 in the Alf group and the Alf + Olm group were significantly higher than those in the 5/6Nx group and the Olm group. In conclusion, the combination of Olm and Alf inhibited the progression of renal damage in the 5/6Nx group through the strong antihypertensive effect as well as the upregulation of the klotho gene.
authors.affiliation: Division of Medicine and Clinical Science, Department of Multidisciplinary Internal Medicine, School of Medicine, Tottori University Faculty of Medicine, Yonago 683-8504, Japan.
authors.forename: Takeaki
authors.initials: T
authors.lastname: Fukui
authors.forename: Chishio
authors.initials: C
authors.lastname: Munemura
authors.forename: Satoko
authors.initials: S
authors.lastname: Maeta
authors.forename: Chihiro
authors.initials: C
authors.lastname: Ishida
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Murawaki
keywords: angiotensin II receptor blocker; chronic renal failure; fibroblast growth factor 23; klothogene; vitamin D
references.citation: J Clin Invest. 2002 Jul;110(2):229-38
references.pmid: 12122115
references.citation: Blood Press. 2005;14(3):184-92
references.pmid: 16036499
references.citation: Kidney Int. 2009 Jan;75(1):88-95
references.pmid: 18843258
references.citation: J Am Soc Nephrol. 2008 Aug;19(8):1613-9
references.pmid: 18463168
references.citation: J Biol Chem. 2011 Mar 11;286(10):8655-8665
references.pmid: 21209102
references.citation: J Biol Chem. 2005 Jan 28;280(4):2543-9
references.pmid: 15531762
references.citation: Hypertension. 1997 Nov;30(5):1289-94
references.pmid: 9369290
references.citation: Hypertension. 2002 Apr;39(4):838-43
references.pmid: 11967236
references.citation: Proc Natl Acad Sci U S A. 2007 Feb 13;104(7):2331-6
references.pmid: 17287345
references.citation: J Steroid Biochem Mol Biol. 2010 Jul;121(1-2):445-7
references.pmid: 20420907
references.citation: J Hypertens. 2009 Oct;27(10):1948-54
references.pmid: 19587609
references.citation: Nefrologia. 2009;29(5):392-6
references.pmid: 19820750
references.citation: Nature. 1997 Nov 6;390(6655):45-51
references.pmid: 9363890
references.citation: Mol Endocrinol. 2003 Dec;17(12):2393-403
references.pmid: 14528024
references.citation: Nature. 1992 Nov 26;360(6402):361-4
references.pmid: 1280332
references.citation: Biochem Biophys Res Commun. 2001 Feb 2;280(4):1015-20
references.pmid: 11162628
references.citation: Am J Nephrol. 2004 Sep-Oct;24(5):503-10
references.pmid: 15452403
references.citation: Biochem Biophys Res Commun. 1998 Aug 28;249(3):865-71
references.pmid: 9731228
references.citation: Lancet. 2010 Nov 6;376(9752):1543-51
references.pmid: 21055801
references.citation: Kidney Int. 2003 Mar;63(3):845-52
references.pmid: 12631065
references.citation: Kidney Int. 2009 Oct;76(7):705-16
references.pmid: 19606082
references.citation: N Engl J Med. 2008 Aug 7;359(6):584-92
references.pmid: 18687639
references.citation: Kidney Int. 2005 Mar;67(3):1171-8
references.pmid: 15698459
references.citation: J Bone Miner Res. 2000 Apr;15(4):770-9
references.pmid: 10780869
references.citation: Biochim Biophys Acta. 2009 Oct;1790(10):1049-58
references.pmid: 19230844
references.citation: Nat Rev Nephrol. 2009 Dec;5(12):691-700
references.pmid: 19859070
references.citation: J Biol Chem. 2006 Mar 10;281(10):6120-3
references.pmid: 16436388
references.citation: Am J Physiol Renal Physiol. 2005 Jul;289(1):F8-28
references.pmid: 15951480
references.citation: Hypertens Res. 2002 May;25(3):447-53
references.pmid: 12135325
references.citation: J Am Soc Nephrol. 2005 Apr;16(4):1115-25
references.pmid: 15728786
references.citation: Kidney Int. 2003 Dec;64(6):2272-9
references.pmid: 14633152