Comparison of acute rapamycin nephrotoxicity with cyclosporine and FK506
Comparison of acute rapamycin nephrotoxicity with cyclosporine and FK506
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DOI：
10.1038/ki.1996.417
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发表时间：
1996-10-01
影响因子：
19.6
通讯作者：
Bennett, WM
中科院分区：
文献类型：
--
作者：
Andoh, TF;Burdmann, EA;Bennett, WM
环孢素A急性肾毒性的特点是肾小球滤过率（GFR）降低、低镁血症和肾小管损伤。CsA的免疫抑制作用和推测其肾毒性的机制是通过抑制肾磷酸酶钙调神经磷酸酶介导的。FK 506（FK），具有不同的化学结构和结合免疫亲和素，也抑制钙调磷酸酶，我们比较了这些药物的肾脏作用的雷帕霉素（RAPA），虽然类似的结构和细胞内结合FK，不通过改变钙调磷酸酶的活性。大鼠皮下注射CsA（15 mg/kg），FK（6 mg/kg/p.o.）。RAPA（3 mg/kg/p.o.）或载体（V）两周。CsA和FK显著降低尿一氧化氮排泄量、肾血流量和GFR，而RAPA则无此作用。相反，所有这三种药物均引起显著的低镁血症，与不适当的高镁排泄分数相关，表明肾镁消耗。此外，所有三种药物均导致大鼠肾脏出现病变，包括肾小管塌陷、空泡化和肾钙质沉着。因此，我们表明，在急性肾毒性实验模型中，只有钙调神经磷酸酶抑制剂才会产生肾小球功能障碍。所有三种免疫抑制药物引起的低镁血症和肾小管损伤的机制尚不清楚，但可能与钙调神经磷酸酶无关。另一方面，肾血管收缩的机制可能与抑制钙调神经磷酸酶有关。
Acute cyclosporine (CsA) nephrotoxicity is characterized by a reduction of glomerular filtration rate (GFR), hypomagnesemia and tubular injury. The mechanisms of CsA's immunosuppressive action and presumably its nephrotoxicity are mediated through inhibition of the renal phosphatase, calcineurin. FK506 (FK), which has a different chemical structure and binding immunuophilin, also inhibits calcineurin, We compared the renal effects of these drugs to those of rapamycin (RAPA), which although similar in structure and intracellular binding to FK, does not work by changing calcineurin activity. Rats were given CsA (15 mg/kg/s.c.), FK (6 mg/kg/p.o.). RAPA (3 mg/kg/p.o.) or vehicle (V) for two weeks on a low salt diet. CsA and FK strikingly decreased urinary excretion of nitric oxide, renal blood How and GFR, whereas RAPA did not. In contrast, all these three drugs caused significant hypomagnesemia associated with inappropriately high fractional excretion of magnesium, suggesting renal magnesium wasting. In addition, with all three drugs there were lesions in the rat kidneys consisting of tubular collapse, vacuolization and nephrocalcinosis. We thus showed that only the calcineurin inhibitors produced glomerular dysfunction in an acute experimental model of nephrotoxicity. The mechanism of hypomagnesemia and tubular injury induced by all three immunosuppressive drags is unclear but may be independent of calcineurin. The mechanism of renal vasoconstriction on the other hand mag. be related to inhibition of calcineurin.