Tacrolimus induces glomerular injury via endothelial dysfunction caused by reactive oxygen species and inflammatory change.
OBJECTIVE
The immunosuppressive drug tacrolimus (FK506) is used clinically to reduce the rejection rate in patients with kidney transplantation; however, the resultant nephrotoxicity remains a serious problem. In the present study we attempted to elucidate the mechanisms of glomerular injury induced by FK506 and the renoprotective effects of the angiotensin II receptor blocker telmisartan.


METHODS
Seven-week-old male Wistar rats were divided into three groups: vehicle group, FK506 group, and FK506 + telmisartan group. After 8 weeks, we assessed kidney function and renal morphological changes including oxidative stress. We also assessed the effect of FK506 in human glomerular endothelial cells (hGECs) with regard to reactive oxygen species (ROS).


RESULTS
FK506 induced ROS production via activation of NAD(P)H oxidase in the glomeruli. Expression of ICAM mRNA was increased in glomeruli from the FK506 group. These effects resulted in macrophage infiltration into the glomeruli. FK506 directly promoted NAD(P)H oxidase activity and accelerated production of ROS in hGECs. Conversely, cotreatment with telmisartan inhibited both NAD(P)H oxidase activity and production of ROS.


CONCLUSIONS
These findings suggest that glomerular injury resulting from FK506 is caused by oxidative stress mediated by activation of NAD(P)H oxidase and that telmisartan exerts a renoprotective effect via antioxidative activity.
Department of Nephrology and Hypertension, Kawasaki Medical School Kurashiki, Okayama, Japan.
Kengo
K
Kidokoro
Minoru
M
Satoh
Hajime
H
Nagasu
Takeo
T
Sakuta
Atsunori
A
Kuwabara
Daisuke
D
Yorimitsu
Yuko
Y
Nishi
Naruya
N
Tomita
Tamaki
T
Sasaki
Naoki
N
Kashihara
D000818:Animals; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007166:Immunosuppressive Agents / Q000633:toxicity*; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D007678:Kidney Glomerulus / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism*; D016559:Tacrolimus / Q000633:toxicity*
D007166:Immunosuppressive Agents; D017382:Reactive Oxygen Species; D016559:Tacrolimus