Department of Nephrology and Hypertension, Kawasaki Medical School Kurashiki, Okayama, Japan.
Kidney Blood Press Res. 2012;35(6):549-57. doi: 10.1159/000339494. Epub 2012 Aug 8.
BACKGROUND/AIMS: 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.
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).
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.
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.
背景/目的：免疫抑制剂他克莫司（FK506）临床上用于降低肾移植患者的排斥率；然而，由此产生的肾毒性仍然是一个严重的问题。本研究旨在阐明 FK506 诱导的肾小球损伤的机制及血管紧张素 II 受体阻滞剂替米沙坦的肾脏保护作用。
将 7 周龄雄性 Wistar 大鼠分为三组：对照组、FK506 组和 FK506+替米沙坦组。8 周后，我们评估了肾功能和肾脏形态学变化，包括氧化应激。我们还评估了 FK506 对人肾小球内皮细胞（hGEC）中活性氧（ROS）的影响。
FK506 通过激活肾小球中的 NAD(P)H 氧化酶诱导 ROS 产生。FK506 组肾小球中 ICAM mRNA 的表达增加。这些作用导致巨噬细胞浸润到肾小球中。FK506 直接促进 NAD(P)H 氧化酶活性并加速 hGEC 中 ROS 的产生。相反，替米沙坦的共同处理抑制了 NAD(P)H 氧化酶活性和 ROS 的产生。
这些发现表明，FK506 引起的肾小球损伤是由 NAD(P)H 氧化酶激活介导的氧化应激引起的，替米沙坦通过抗氧化活性发挥肾脏保护作用。
