关键词： AHR ANOVA BCRP CKD Ct E(1)S EDX EM FVB Gapdh HE stain HEK293 cells Hyperuricemia IC(50) IDO Kim-1 Kynurenic acid LC–MS/MS MRP4 MTX Ngal OAT Oxonic acid SEM SLC SNP URAT1 analysis of variance aryl hydrocarbon receptor breast cancer resistance protein chronic kidney disease cycle threshold eYFP electron microscopy energy-dispersive X-ray enhanced yellow fluorescent protein estrone sulphate friend leukemia virus B glyceraldehyde-3-phosphate dehydrogenase half maximal inhibitory concentration hematoxylin and eosin stain human embryonic kidney cells indoleamine 2,3-dioxygenase kidney injury molecule-1 liquid chromatography-tandem mass spectrometry methotrexate multidrug resistance protein 4 neutrophil gelatinase-associated lipocalin organic anion transporter single nucleotide polymorphism solute carrier family standard error of mean urate transporter 1

Mesh ： ATP Binding Cassette Transporter, Subfamily G, Member 2 ATP-Binding Cassette Transporters / antagonists & inhibitors Acute-Phase Proteins / metabolism Biological Transport HEK293 Cells Humans Hyperuricemia / chemically induced metabolism Kynurenic Acid / metabolism Lipocalin-2 Lipocalins / metabolism Multidrug Resistance-Associated Proteins / antagonists & inhibitors Neoplasm Proteins / antagonists & inhibitors Oxonic Acid / administration & dosage Proto-Oncogene Proteins / metabolism Tryptophan / metabolism Uric Acid / metabolism

来  源：   DOI：10.1016/j.bbadis.2013.05.002   PDF(Sci-hub)

Abstract：
Hyperuricemia is related to a variety of pathologies, including chronic kidney disease (CKD). However, the pathophysiological mechanisms underlying disease development are not yet fully elucidated. Here, we studied the effect of hyperuricemia on tryptophan metabolism and the potential role herein of two important uric acid efflux transporters, multidrug resistance protein 4 (MRP4) and breast cancer resistance protein (BCRP). Hyperuricemia was induced in mice by treatment with the uricase inhibitor oxonic acid, confirmed by the presence of urate crystals in the urine of treated animals. A transport assay, using membrane vesicles of cells overexpressing the transporters, revealed that uric acid inhibited substrate-specific transport by BCRP at clinically relevant concentrations (calculated IC50 value: 365±13μM), as was previously reported for MRP4. Moreover, we identified kynurenic acid as a novel substrate for MRP4 and BCRP. This finding was corroborated by increased plasma levels of kynurenic acid observed in Mrp4(-/-) (107±19nM; P=0.145) and Bcrp(-/-) mice (133±10nM; P=0.0007) compared to wild type animals (71±11nM). Hyperuricemia was associated with >1.5 fold increase in plasma kynurenine levels in all strains. Moreover, hyperuricemia led to elevated plasma kynurenic acid levels (128±13nM, P=0.005) in wild type mice but did not further increase kynurenic acid levels in knockout mice. Based on our results, we postulate that elevated uric acid levels hamper MRP4 and BCRP functioning, thereby promoting the retention of other potentially toxic substrates, including kynurenic acid, which could contribute to the development of CKD.
摘要：
高尿酸血症与多种病理有关，包括慢性肾病（CKD）。然而,疾病发展的病理生理机制尚未完全阐明。这里,我们研究了高尿酸血症对色氨酸代谢的影响以及两种重要的尿酸外排转运蛋白的潜在作用，多药耐药蛋白4（MRP4）和乳腺癌耐药蛋白（BCRP）。高尿酸血症是通过尿酸酶抑制剂氧代酸来诱导小鼠，通过治疗动物的尿液中尿酸盐晶体的存在证实。运输试验，使用过表达转运蛋白的细胞膜囊泡，显示尿酸在临床相关浓度下抑制BCRP的底物特异性转运（计算的IC50值：365±13μM），如先前报道的MRP4。此外，我们确定犬尿烯酸是MRP4和BCRP的新底物.与野生型动物(71±11nM)相比,在Mrp4(-/-)(107±19nM;P=0.145)和Bcrp(-/-)小鼠(133±10nM;P=0.0007)中观察到的犬尿氨酸的血浆水平增加证实了这一发现。在所有菌株中,高尿酸血症与血浆犬尿氨酸水平的>1.5倍增加相关。此外，高尿酸血症导致血浆犬尿氨酸水平升高（128±13nM，在野生型小鼠中P=0.005),但在敲除小鼠中没有进一步增加犬尿氨酸水平。根据我们的结果,我们假设尿酸水平升高会妨碍MRP4和BCRP的功能，从而促进其他潜在有毒底物的保留，包括犬尿酸,有助于CKD的发展。
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