Angiotensin II blockade upregulates the expression of Klotho, the anti-ageing gene, in an experimental model of chronic cyclosporine nephropathy.
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.
Yoon
Hye Eun
HE
Division of Nephrology, Department of Internal Medicine, Incheon St Mary’s Hospital, College of Medicine, The Catholic University of Korea, Incheon, South Korea.
Ghee
Jung Yeon
JY
Piao
ShangGuo
S
Song
Ji-Hyun
JH
Han
Dong He
DH
Kim
Sol
S
Ohashi
Naro
N
Kobori
Hiroyuki
H
Kuro-o
Makoto
M
Yang
Chul Woo
CW
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
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
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