title: Angiotensin II blockade upregulates the expression of Klotho, the anti-ageing gene, in an experimental model of chronic cyclosporine nephropathy.
abstract: BACKGROUND
  The Klotho gene plays a role in suppressing ageing-related disorders. It is suggested that activation of renin-angiotensin system (RAS) or oxidative stress suppresses Klotho in the kidney. This study evaluated the association between Klotho expression and RAS in cyclosporine (CsA)-induced renal injury.
  
  
  METHODS
  Chronic CsA nephropathy was induced by administering CsA (30 mg/kg) to mice on a low-salt diet (LSD) for 4 weeks. A normal-salt diet (NSD) was used as the control. Reverse transcription-polymerase chain reaction, western blot and immunohistochemistry were performed for Klotho and intrarenal RAS activity was measured using immunohistochemistry for angiotensinogen and renin. Oxidative stress was measured with urinary excretion of 8-hydroxy-2'-deoxyguanosine (8-OHdG).
  
  
  RESULTS
  CsA treatment decreased Klotho mRNA and protein in mouse kidney in a dose-dependent and time-dependent manner, but a concurrent treatment with losartan, an angiotensin II type 1 (AT1) receptor blocker, reversed the decrease in Klotho expression with histological improvement. This finding was more marked in the LSD than the NSD. Klotho expression was correlated with angiotensinogen and renin expression, tubulointerstitial fibrosis score and urinary 8-OHdG excretion.
  
  
  CONCLUSIONS
  Angiotensin II may play a pivotal role in regulating Klotho expression in CsA-induced renal injury. AT1 receptor blocker may inhibit the ageing process by decreasing oxidative stress caused by CsA.
authors.affiliation: Division of Nephrology, Department of Internal Medicine, Incheon St Mary’s Hospital, College of Medicine, The Catholic University of Korea, Incheon, South Korea.
authors.forename: Hye Eun
authors.initials: HE
authors.lastname: Yoon
authors.forename: Jung Yeon
authors.initials: JY
authors.lastname: Ghee
authors.forename: ShangGuo
authors.initials: S
authors.lastname: Piao
authors.forename: Ji-Hyun
authors.initials: JH
authors.lastname: Song
authors.forename: Dong He
authors.initials: DH
authors.lastname: Han
authors.forename: Sol
authors.initials: S
authors.lastname: Kim
authors.forename: Naro
authors.initials: N
authors.lastname: Ohashi
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kobori
authors.forename: Makoto
authors.initials: M
authors.lastname: Kuro-o
authors.forename: Chul Woo
authors.initials: CW
authors.lastname: Yang
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D000375:Aging / Q000187:drug effects*; D000804:Angiotensin II / Q000037:antagonists & inhibitors*; D000818:Animals; D015153:Blotting, Western; D002908:Chronic Disease; D016572:Cyclosporine / Q000009:adverse effects*; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000652:urine; D004195:Disease Models, Animal; D005966:Glucuronidase / Q000235:genetics / Q000378:metabolism*; D007124:Immunoenzyme Techniques; D007166:Immunosuppressive Agents / Q000009:adverse effects*; D007674:Kidney Diseases / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D000090265:Klotho Proteins; D008297:Male; D051379:Mice; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation; D014662:Vasoconstrictor Agents / Q000037:antagonists & inhibitors
chemical_list: D007166:Immunosuppressive Agents; D012333:RNA, Messenger; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D016572:Cyclosporine; D000080242:8-Hydroxy-2'-Deoxyguanosine; D005966:Glucuronidase; D000090265:Klotho Proteins; D003849:Deoxyguanosine
references.citation: FASEB J. 2003 Jun;17(9):1096-8
references.pmid: 12709417
references.citation: Biochem Biophys Res Commun. 1998 Aug 28;249(3):865-71
references.pmid: 9731228
references.citation: Nephron Exp Nephrol. 2005;99(1):e9-16
references.pmid: 15637465
references.citation: Korean J Intern Med. 2009 Jun;24(2):81-92
references.pmid: 19543484
references.citation: J Biol Chem. 2005 Nov 11;280(45):38029-34
references.pmid: 16186101
references.citation: FEBS Lett. 2003 Sep 11;551(1-3):58-62
references.pmid: 12965205
references.citation: Vascul Pharmacol. 2009 May-Jun;50(5-6):185-93
references.pmid: 19563735
references.citation: Cell Mol Life Sci. 2000 May;57(5):738-46
references.pmid: 10892340
references.citation: Am J Hypertens. 2000 Dec;13(12):1301-7
references.pmid: 11130775
references.citation: Kidney Int. 1996 Oct;50(4):1089-100
references.pmid: 8887265
references.citation: J Am Soc Nephrol. 1993 Aug;4(2):214-21
references.pmid: 8400085
references.citation: Am J Transplant. 2002 May;2(5):391-9
references.pmid: 12123203
references.citation: Hypertension. 2001 Nov;38(5):1130-6
references.pmid: 11711510
references.citation: Kidney Int. 1988 Feb;33(2):590-600
references.pmid: 3283402
references.citation: Am J Kidney Dis. 2000 Feb;35(2):333-46
references.pmid: 10676738
references.citation: Am J Physiol Renal Physiol. 2006 Nov;291(5):F1052-60
references.pmid: 16735462
references.citation: Cell Death Differ. 2007 Jun;14(6):1181-90
references.pmid: 17363962
references.citation: Biochem Biophys Res Commun. 2001 Feb 2;280(4):1015-20
references.pmid: 11162628
references.citation: J Nephrol. 2002 Jul-Aug;15(4):358-67
references.pmid: 12243364
references.citation: Br J Pharmacol. 2000 Jul;130(6):1339-47
references.pmid: 10903974
references.citation: Nephron Exp Nephrol. 2005;101(2):e67-74
references.pmid: 15976510
references.citation: Nephrol Dial Transplant. 2005 Dec;20(12):2636-45
references.pmid: 16204278
references.citation: Exp Gerontol. 2008 Oct;43(10):919-28
references.pmid: 18765277
references.citation: Cell Metab. 2009 May;9(5):403-5
references.pmid: 19416709
references.citation: Am J Physiol. 1993 Jul;265(1 Pt 1):C15-8
references.pmid: 8338123
references.citation: Clin Exp Hypertens. 1998 Nov;20(8):867-84
references.pmid: 9817607
references.citation: Kidney Int. 2000 May;57(5):1803-17
references.pmid: 10792600
references.citation: J Am Soc Nephrol. 2001 Apr;12(4):822-827
references.pmid: 11274244
references.citation: Curr Drug Metab. 2002 Feb;3(1):61-71
references.pmid: 11876576
references.citation: Circ Res. 1990 Oct;67(4):871-85
references.pmid: 2145091
references.citation: Hypertension. 1999 Jan;33(1 Pt 2):225-31
references.pmid: 9931109
references.citation: Hypertension. 2002 Apr;39(4):838-43
references.pmid: 11967236
references.citation: Am J Transplant. 2005 Jun;5(6):1375-82
references.pmid: 15888044
references.citation: Regul Pept. 2005 Jun 30;128(3):247-52
references.pmid: 15837534
references.citation: Hypertension. 2004 May;43(5):1126-32
references.pmid: 15037565
references.citation: Hypertension. 1999 Sep;34(3):496-502
references.pmid: 10489400
references.citation: J Clin Invest. 2009 Mar;119(3):524-30
references.pmid: 19197138
references.citation: Circulation. 2004 Apr 13;109(14):1776-82
references.pmid: 15037532
references.citation: J Hypertens. 2002 Dec;20(12):2487-94
references.pmid: 12473874
references.citation: J Hypertens. 2001 Aug;19(8):1403-9
references.pmid: 11518848
references.citation: Ren Fail. 2004 Sep;26(5):467-77
references.pmid: 15526904
references.citation: Yonsei Med J. 2004 Dec 31;45(6):1004-16
references.pmid: 15627291
references.citation: Am J Physiol Renal Physiol. 2007 Sep;293(3):F831-8
references.pmid: 17596534
references.citation: Kidney Int. 2002 Jul;62(1):78-85
references.pmid: 12081566
references.citation: Proc Natl Acad Sci U S A. 1989 Dec;86(24):9697-701
references.pmid: 2602371
references.citation: Transplantation. 2007 Apr 15;83(7):938-47
references.pmid: 17460566
references.citation: Cardiovasc Res. 2004 Nov 1;64(2):331-6
references.pmid: 15485693
references.citation: Transplantation. 2005 Sep 15;80(5):691-9
references.pmid: 16177646
references.citation: Circulation. 2006 Sep 12;114(11):1159-68
references.pmid: 16952979
references.citation: J Am Soc Nephrol. 1995 Oct;6(4):1186-96
references.pmid: 8589285
references.citation: J Pharmacol Exp Ther. 1993 Jun;265(3):1047-54
references.pmid: 7685382
references.citation: Am J Physiol Renal Physiol. 2008 Sep;295(3):F772-9
references.pmid: 18579707
references.citation: Antioxid Redox Signal. 2003 Dec;5(6):691-7
references.pmid: 14588141
references.citation: Transplantation. 2003 Feb 15;75(3):309-15
references.pmid: 12589150
references.citation: Nature. 1997 Nov 6;390(6655):45-51
references.pmid: 9363890
references.citation: Science. 2005 Sep 16;309(5742):1829-33
references.pmid: 16123266
references.citation: Kidney Int. 2001 Sep;60(3):847-57
references.pmid: 11532080
references.citation: Hear Res. 2002 Sep;171(1-2):103-110
references.pmid: 12204354
references.citation: Res Commun Chem Pathol Pharmacol. 1990 May;68(2):189-203
references.pmid: 2162073
references.citation: Nephrol Dial Transplant. 2004 Sep;19(9):2217-22
references.pmid: 15266031