Kidney-specific Dysfunction of the Organic Anion Transporter MRP2 (ABCC2): Functional Consequences for Renal Grafts. Rattus norvegicus

Transplanting renal allografts represents the major curative treatment of chronic renal failure. Despite recent advances in immunosuppressive therapy, long-term survival of allografts remains a major clinical problem. Kidney function depends in part on transport proteins such as MRP2 (ABCC2) which facilitates renal secretion of amphiphilic exogenous and endogenous compounds. Inherited variants of genes not related to the immune system have been shown to modify the outcome after renal transplantation. We investigated whether ABCC2 gene variants in the donor kidney affect renal graft function. A congenic rat model was established carrying a single nucleotide deletion in the ABCC2 gene. Renal cross transplantations were performed with wild type rats. Renal excretion of the MRP2 substrates bilirubin glucuronide and p-aminohippuric acid, but not morphine-6-glucuronide, was affected by the donor genotype. Moreover, proteomic analyses and transcriptional profiling revealed modified expression patterns indicative of increased oxidative stress in renal grafts carrying the mutated gene. In the clinical part our study, we assessed ABCC2 haplotypes in renal transplant patients and evaluated graft function. The 3563T>A gene polymorphism was significantly associated with delayed graft function. Together, both experimental and clinical data show that the ABCC2 genotype of the donor kidney affects renal graft function. Keywords: dysfunction of organic anion transporter MRP2 (ABCC2) Overall design: Performed analyses of (6) wild-type and (6) MRP2 deficient kidneys that had been transplanted in wild-type recipients.

肾同种异体移植是慢性肾衰竭的主要治愈性治疗手段。尽管免疫抑制疗法近年来取得长足进展，但同种异体移植物的长期存活仍是临床亟待解决的重大问题。肾脏功能部分依赖于MRP2（ABCC2）这类转运蛋白，该蛋白可介导肾分泌两亲性外源性与内源性化合物。已有研究证实，非免疫相关基因的遗传变异可改变肾移植术后的结局。本研究旨在探究供体肾脏中的ABCC2基因变异是否会影响肾移植物功能。

本研究构建了ABCC2基因携带单核苷酸缺失的同源近交大鼠模型，并采用野生型大鼠开展肾交叉移植实验。结果显示，供体基因型会影响MRP2底物胆红素葡糖醛酸苷与对氨基马尿酸的肾排泄，但对吗啡-6-葡糖醛酸苷的肾排泄无显著影响。此外，蛋白质组学分析与转录组谱分析结果表明，携带突变基因的肾移植物中出现了提示氧化应激增强的表达模式改变。

在本研究的临床部分，我们对肾移植患者的ABCC2单倍型进行了评估，并分析了移植物功能。结果发现，3563T>A基因多态性与移植物功能延迟恢复显著相关。

综上，实验与临床数据均表明，供体肾脏的ABCC2基因型可影响肾移植物功能。

关键词：有机阴离子转运蛋白MRP2（ABCC2）功能异常
整体实验设计：对6例野生型和6例MRP2缺陷型肾脏开展分析，上述肾脏均移植于野生型受体大鼠体内。