Nakatani Tatsuya, Uchida Junji, Iwai Tomoaki, Matsumura Kentaro, Naganuma Toshihide, Kuratsukuri Katsuyuki, Sugimura Kazunobu
Department of Urology, Osaka City University Graduate School of Medicine, Osaka, Japan.
Int J Mol Med. 2003 Jan;11(1):75-8.
Tacrolimus is a superior immunosuppressive agent and has markedly improved the short-term outcome of renal allografts. Despite the beneficial effects of maintaining immunotolerance in organ transplant recipients, it has well-characterized side effects on renal hemodynamics in the early phase. The mechanism of tacrolimus-induced acute nephrotoxicity is still unclear. The purpose of this study was to elucidate the role of renin-angiotensin system (RAS) in tacrolimus-induced acute nephrotoxicity. We examined the renal mRNA levels of renin in order to elucidate the relationship between plasma renin activity (PRA) and tacrolimus-induced renal dysfunction. Daily administration of tacrolimus (4 mg/kg/day) for 2 weeks in spontaneously hypertensive rats (SHR) significantly increased BUN and plasma creatinine (P-Cr) level, while endogenous creatinine clearance (Ccr) significantly decreased in tacrolimus treated rats. Regarding tubular function data, fractional excretion of Na (FENa) and fractional excretion of K were higher in the tacrolimus treated group. Renin mRNA levels in the renal cortex in tacrolimus treated rats significantly increased when compared to the vehicle-treated rats. Ccr level was inversely proportional to PRA, with a high correlation coeffecient. The rise in PRA significantly correlated with increase in FENa by liner regression. Therefore, the results indicate that RAS is involved in the tacrolimus-induced acute nephrotoxicity.
他克莫司是一种卓越的免疫抑制剂，显著改善了肾移植的短期预后。尽管在器官移植受者中维持免疫耐受有诸多益处，但它在早期对肾血流动力学有明确的副作用。他克莫司诱导急性肾毒性的机制仍不清楚。本研究的目的是阐明肾素 - 血管紧张素系统（RAS）在他克莫司诱导的急性肾毒性中的作用。我们检测了肾素的肾mRNA水平，以阐明血浆肾素活性（PRA）与他克莫司诱导的肾功能障碍之间的关系。在自发性高血压大鼠（SHR）中每日给予他克莫司（4mg/kg/天），持续2周，显著增加了血尿素氮（BUN）和血浆肌酐（P-Cr）水平，而在他克莫司治疗的大鼠中内源性肌酐清除率（Ccr）显著降低。关于肾小管功能数据，他克莫司治疗组的钠分数排泄（FENa）和钾分数排泄更高。与载体处理的大鼠相比，他克莫司治疗的大鼠肾皮质中的肾素mRNA水平显著增加。Ccr水平与PRA呈负相关，相关系数高。通过线性回归分析，PRA的升高与FENa的增加显著相关。因此，结果表明RAS参与了他克莫司诱导的急性肾毒性。
