Departamento de Nefrologia (LIM 12), Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brasil.
Braz J Med Biol Res. 2010 Aug;43(8):737-44. doi: 10.1590/s0100-879x2010007500058. Epub 2010 Jun 18.
Calcineurin inhibitors exacerbate ischemic injury in transplanted kidneys, but it is not known if sirolimus protects or exacerbates the transplanted kidney from ischemic injury. We determined the effects of sirolimus alone or in combination with cyclosporin A (CsA) on oxygenated and hypoxic/reoxygenated rat proximal tubules in the following in vitro groups containing 6-9 rats per group: sirolimus (10, 50, 100, 250, 500, and 1000 nanog/mL); CsA (100 microg/mL); sirolimus (50 and 250 nanog/mL) + CsA (100 microg/mL); control; vehicle (20% ethanol). For in vivo studies, 3-week-old Wistar rats (150-250 g) were submitted to left nephrectomy and 30-min renal artery clamping. Renal function and histological evaluation were performed 24 h and 7 days after ischemia (I) in five groups: sham, I, I + SRL (3 mg x kg(-1) x day(-1), po), I + CsA (3 mg x kg(-1) x day(-1), sc), I + SRL + CsA. Sirolimus did not injure oxygenated or hypoxic/reoxygenated proximal tubules and did not potentiate the tubular toxic effects of CsA. Neither drug affected the glomerular filtration rate (GFR) at 24 h. GFR was reduced in CsA-treated rats on day 7 (0.5 +/- 0.1 mL/min) but not in rats receiving sirolimus + CsA (0.8 +/- 0.1 mL/min) despite the reduction in renal blood flow (3.9 +/- 0.5 mL/min). Acute tubular necrosis regeneration was similar for all groups. Sirolimus alone was not toxic and did not enhance hypoxia/reoxygenation injury or CsA toxicity to proximal tubules. Despite its hemodynamic effects, sirolimus protected post-ischemic kidneys against CsA toxicity.
钙调磷酸酶抑制剂可加重移植肾的缺血性损伤，但尚不清楚西罗莫司是否能保护或加重移植肾的缺血性损伤。我们在以下 6-9 只大鼠/组的体外分组中，分别测定了西罗莫司单独或与环孢素 A（CsA）联合应用对氧合和缺氧/复氧的大鼠近端肾小管的作用：西罗莫司（10、50、100、250、500 和 1000 纳克/毫升）；CsA（100 微克/毫升）；西罗莫司（50 和 250 纳克/毫升）+CsA（100 微克/毫升）；对照；载体（20%乙醇）。在体内研究中，3 周龄 Wistar 大鼠（150-250 克）接受左肾切除术和 30 分钟的肾动脉夹闭。在缺血（I）后 24 小时和 7 天，对 5 个组的肾功能和组织学评估：假手术组、I 组、I+SRL（3 毫克 x 千克(-1) x 天(-1)，口服）、I+CsA（3 毫克 x 千克(-1) x 天(-1)，皮下）、I+SRL+CsA。西罗莫司未损伤氧合或缺氧/复氧的近端肾小管，也未增强 CsA 的肾小管毒性作用。两种药物均未在 24 小时内影响肾小球滤过率（GFR）。CsA 治疗的大鼠在第 7 天 GFR 降低（0.5 +/- 0.1 毫升/分钟），但接受西罗莫司+CsA 的大鼠 GFR 未降低（0.8 +/- 0.1 毫升/分钟），尽管肾血流量减少（3.9 +/- 0.5 毫升/分钟）。急性肾小管坏死再生在所有组中均相似。西罗莫司单独应用无毒性，且不加重缺氧/复氧损伤或 CsA 对近端肾小管的毒性。尽管西罗莫司具有血液动力学作用，但它可保护缺血后肾脏免受 CsA 毒性的影响。
