Expression of multidrug resistance P-glycoprotein in kidney allografts from cyclosporine A-treated patients
Expression of multidrug resistance P-glycoprotein in kidney allografts from cyclosporine A-treated patients
复制标题
DOI：
10.1046/j.1523-1755.2001.00782.x
复制
发表时间：
2001-07-01
影响因子：
19.6
通讯作者：
Hauser, IA
中科院分区：
文献类型：
--
作者：
Koziolek, MJ;Riess, R;Hauser, IA
背景资料。多药耐药(MDR)基因产物P-糖蛋白(P-gp)是疏水性、潜在毒性化合物的跨膜外排泵。包括免疫抑制剂环孢素A(CsA)。我们先前已经证明CsA在体外能增加近曲小管和内皮细胞中P-gp的表达。本研究的目的是研究在接受CsA治疗的患者的移植肾活检中这些观察结果的活体相关性。用两种不同的单抗(UIC2和MRK16)对石蜡切片进行免疫组化检测P-gp的表达。取自具有不同组织病理学诊断的CsA治疗的肾移植患者的活检组织(N=79)，并与来自正常人肾脏的活检组织(N=13)或来自无CsA免疫抑制的同种异体移植肾的活检组织(N=15)进行比较。此外，对10个供体肾脏在植入前和排斥期间(“零活检”)的活检进行了调查。急性肾小管坏死(ATN：N=10)患者经CsA治疗后，动脉内皮细胞P-gp表达显著增加。CsA肾毒性组(N=19)近端肾小管和鲍曼囊(BC)上皮细胞表达P-gp，而对照组P-gp表达较少。CsA后急性细胞性排斥反应(N=30)、血管排斥反应(N=10)或慢性移植物肾病(N=10)与白细胞P-gp表达增强和动脉内皮细胞P-gp表达增加有关。近端小管和BC。相比之下。与对照组相比，接受不含CsA免疫抑制方案治疗的患者的活检组织中P-gp表达没有增加。零活检显示P-gp在肾小管弱、均匀、非极化的表达，而在CsA治疗后，P-gp在刷状缘动脉内皮细胞中的表达增加。和BC。结论。CsA治疗与ATN肾移植肾实质细胞P-gp表达增加有关。急性或慢性移植排斥反应，但P-gp在CsA肾毒性患者中不升高。提示CsA可通过P-gp自身解毒，肾实质细胞P-gp表达上调不足是CsA肾毒性的原因之一。P-gp在浸润性白细胞中的表达增加与同种异体排斥反应的严重程度相关，提示P-gp可能降低CsA的免疫抑制效果。因此，CsA暴露的肾实质细胞和/或浸润性白细胞的P-gp诱导反应的个体差异可能分别导致CsA的肾毒性或排斥反应。
Background. The multidrug resistance (MDR) gene product P-glycoprotein (P-gp) is a transmembrane efflux pump for hydrophobic, potentially toxic compounds. including the immunosuppressant cyclosporine A (CsA). We have previously shown that CsA increases P-gp expression in proximal tubule and endothelial cells in vitro. The aim of the present study was to investigate the in vivo relevance of these observations in renal allograft biopsies from CsA-treated patients.Methods. P-gp expression was determined by immunohistochemistry of paraffin sections using two different monoclonal antibodies (UIC2 and MRK16). Biopsies were taken from CsA treated renal transplant patients with different histopathological diagnoses (N = 79) and were compared with biopsies from normal human kidneys (N = 13) or with allograft biopsies from patients under a CsA-free immunosuppression (N = 15). More over, biopsies from 10 donor kidneys before implantation and during rejection episodes ("zero biopsies") were investigated.Results. P-gp expression in biopsies with acute tubular necrosis (ATN: N = 10) after CsA treatment was significantly higher in arterial endothelia. proximal tubules and epithelial cells of Bowman's capsule (BC), whereas P-gp was sparsely induced in CsA nephrotoxicity (N = 19) compared with controls. Acute cellular (N = 30) and vascular rejection (N = 10) or chronic allograft nephropathy (N = 10) after CsA was associated with strong P-gp expression in infiltrating leukocytes and increased P-gp expression in arterial endothelia. proximal tubules, and BC. In contrast. biopsies of patients treated with a CsA-free immunosuppression regimen did not show increases in P-gp expression compared with controls. Zero biopsies showed a weak, homogeneous, nonpolarized expression of P-gp in tubules and an increased expression of P-gp after CsA therapy in the brush border, arterial endothelia. and BC.Conclusions. CsA treatment was associated with increased P-gp expression in parenchymal cells of kidney transplants with ATN. acute or chronic transplant rejection, but P-gp was not increased in patients with CsA nephrotoxicity. This indicates that CsA induces its own detoxification by P-gp and that inadequate up-regulation of P-gp in renal parenchymal cells contributes to CsA nephrotoxicity. Increased expression of P-gp in infiltrating leukocytes correlated with the severity of allograft rejection, suggesting that P-gp may decrease the immunosuppressive efficacy of CsA. Thus, individual differences in the P-gp induction response of CsA-exposed renal parenchymal cells and/or infiltrating leukocytes may predispose to either CsA nephrotoxicity or rejection, respectively.