Effect of sirolimus on calcineurin inhibitor-induced nephrotoxicity using renal expression of KLOTHO, an antiaging gene.
BACKGROUND
The aim of this study was to observe the effect of sirolimus (SRL) on calcineurin inhibitor (CNI)-induced nephrotoxicity in the aging process by using renal expression of KLOTHO, an antiaging gene. METHODS.: Mice were treated with vehicle (VH; 1 mL/kg/day of olive oil), cyclosporine A (CsA; 30 mg/kg/day), or tacrolimus (FK; 1 mg/kg/day) with or without SRL (0.3 mg/kg/day) for 2 weeks. KLOTHO expression was evaluated by using reverse-transcriptase polymerase chain reaction, immunoblotting, and immunohistochemistry. Oxidative stress was evaluated by using immunohistochemistry and urinary excretion of 8-hydroxy-2'-deoxyguanosine (8-OHdG). The calcium metabolism was evaluated by using renal ectopic calcification, serum intact parathyroid hormone level, and renal fibroblast factor 23 (FGF23) expression.


RESULTS
Treatment with CsA or FK alone significantly decreased KLOTHO expression and increased urinary 8-OHdG excretion compared with VH treatment but SRL treatment did not. Treatment SRL+CsA or SRL+FK further decreased KLOTHO expression and increased urinary 8-OHdG excretion compared with treatment of CsA or FK alone. There was a strong correlation between KLOTHO expression and urinary 8-OHdG excretion (r=-0.893; P<0.001). Treatment of CsA or FK alone increased renal ectopic calcification and serum intact parathyroid hormone level and decreased renal FGF23 expression compared with VH treatment (P<0.05) but SRL treatment did not. Treatment with SRL+CNI aggravated these parameters compared with CNI alone.


CONCLUSIONS
SRL accelerates the CNI-induced oxidative process by down-regulating the renal antioxidant KLOTHO expression in the kidney.
Han
Dong He
DH
Department of Internal Medicine, The Catholic University of Korea, Seoul, Korea.
Piao
Shang Guo
SG
Song
Ji-Hyun
JH
Ghee
Jung Yeon
JY
Hwang
Hyeon Seok
HS
Choi
Bum Soon
BS
Kim
Jin
J
Yang
Chul Woo
CW
D000375:Aging / Q000235:genetics*; D000818:Animals; D065095:Calcineurin Inhibitors; D005576:Colforsin / Q000494:pharmacology; D016572:Cyclosporine / Q000494:pharmacology; D017931:DNA Primers; D000089703:Fibroblast Growth Factor-23; D005786:Gene Expression Regulation / Q000187:drug effects; D005966:Glucuronidase / Q000235:genetics*; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007668:Kidney / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D000090265:Klotho Proteins; D051379:Mice; D009395:Nephritis, Interstitial / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects; D012313:RNA / Q000235:genetics / Q000302:isolation & purification; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020123:Sirolimus / Q000494:pharmacology*; D016559:Tacrolimus / Q000494:pharmacology
D065095:Calcineurin Inhibitors; D017931:DNA Primers; C000717428:Fgf23 protein, mouse; D007166:Immunosuppressive Agents; D012333:RNA, Messenger; D005576:Colforsin; D012313:RNA; D000089703:Fibroblast Growth Factor-23; D016572:Cyclosporine; D005966:Glucuronidase; D000090265:Klotho Proteins; D020123:Sirolimus; D016559:Tacrolimus