Analysis of ABCG2 and other urate transporters in uric acid homeostasis in chronic kidney disease: potential role of remote sensing and signaling.
Analysis of ABCG2 and other urate transporters in uric acid homeostasis in chronic kidney disease: potential role of remote sensing and signaling.
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DOI：
10.1093/ckj/sfw010
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发表时间：
2016-06
影响因子：
4.6
通讯作者：
Nigam SK
中科院分区：
文献类型：
--
作者：
Bhatnagar V;Richard EL;Wu W;Nievergelt CM;Lipkowitz MS;Jeff J;Maihofer AX;Nigam SK
在慢性肾脏疾病(CKD)的背景下，改变肾外尿酸的处理可能是调节血浆尿酸的必要手段。遥测和信号假说(Nigam S.)药物转运蛋白到底是做什么的？NAT Rev Drug Discov 2015；14：29-44)表明，不同组织中的多特异性溶质载体(SLC)和ATP结合盒(ABC)药物转运体是器官间通讯系统的一部分，该系统在器官损伤后维持尿酸盐和其他代谢物的水平。利用慢性肾功能不全队列(CRIC；n=3598)的资料，研究血尿酸与下列尿酸转运蛋白的单核苷酸多态(SNPs)的关系：ABCG2(BRCP)、SLC22A6(OAT1)、SLC22A8(OAT3)、SLC22A10(OAT5)、SLC22A11(OAT4)、SLC22A12(URAT1)、SLC22A13(OAT10)、SLC17A1-A3(NPTS)、SLC2A9(GLUT9)、ABCC2(MRP2)和ABCC4(MRP4)。对于欧洲血统(EA)和非洲血统(AA)的主成分，控制了年龄、性别和肾功能的主成分分别运行回归模型，并对多次比较进行了P值校正。电针受试者和肾功能正常的双胞胎队列用于比较。在CRICEA基因中，ABCG2(rs4148157；β系数=0.68；P=4.78E-13)和SLC2A9(rs13125646；β系数=−0.30；P=1.06E-5)有显著差异。在AA中，SLC2A9的SNPs信号最强(但没有统计学意义)，其次是ABCG2的SNPs。在双生子研究(肾功能正常)中，只有SLC2A9的SNP有统计学意义(rs4481233；β系数=−0.45；P=7.0E-6)。在CRIC中，SLC17A3(NPT4)的相关性也较弱，SLC22A8(OAT3)、SLC22A11(OAT4)和ABCC4(MRP4)的性别特定关联也被发现。在EA合并CKD(CRIC队列)的患者中，我们发现ABCG2上的SNPs与尿酸显著相关，ABCG2是尿酸通过肠道的关键转运体。与ABCG2相比，SLC2A9在这一亚组CKD患者中的作用要小得多。其他SLC(如SLC22A8或OAT3)和ABC(如ABCC4或MRP4)基因中的SNPs似乎对CKD的尿酸稳态有微弱的性别依赖性贡献。由于肾脏尿酸盐转运在肾功能下降的情况下受到影响，肾外ABCG2似乎起到了代偿作用--这一概念与动物研究和遥感与信号假说一致。总体而言，这些数据表明，不同的尿酸盐转运体如何根据肾功能、种族和性别而变得更重要或更不重要。侧重于加强ABCG2尿酸盐处理的治疗可能有助于CKD和高尿酸血症的发生。
In the setting of chronic kidney disease (CKD), altered extra-renal urate handling may be necessary to regulate plasma uric acid. The Remote Sensing and Signaling Hypothesis (Nigam S. What do drug transporters really do? Nat Rev Drug Discov 2015; 14: 29–44) suggests that multispecific solute carrier (SLC) and ATP-binding cassette (ABC) drug transporters in different tissues are part of an inter-organ communication system that maintains levels of urate and other metabolites after organ injury. Data from the Chronic Renal Insufficiency Cohort (CRIC; n = 3598) were used to study associations between serum uric acid and single nucleotide polymorphisms (SNPs) on the following uric acid transporters: ABCG2 (BRCP), SLC22A6 (OAT1), SLC22A8 (OAT3), SLC22A10 (OAT5), SLC22A11 (OAT4), SLC22A12 (URAT1), SLC22A13 (OAT10), SLC17A1-A3 (NPTs), SLC2A9 (GLUT9), ABCC2 (MRP2) and ABCC4 (MRP4). Regression models, controlling for principal components age, gender and renal function, were run separately for those of European (EA) and African ancestry (AA), and P-values corrected for multiple comparisons. A twin cohort with participants of EA and normal renal function was used for comparison. Among those of EA in CRIC, statistically significant signals were observed for SNPs in ABCG2 (rs4148157; beta-coefficient = 0.68; P = 4.78E-13) and SNPs in SLC2A9 (rs13125646; beta-coefficient = −0.30; P = 1.06E-5). Among those of AA, the strongest (but not statistically significant) signals were observed for SNPs in SLC2A9, followed by SNPs in ABCG2. In the twin study (normal renal function), only SNPs in SLC2A9 were significant (rs4481233; beta-coefficient=−0.45; P = 7.0E-6). In CRIC, weaker associations were also found for SLC17A3 (NPT4) and gender-specific associations found for SLC22A8 (OAT3), SLC22A11 (OAT4), and ABCC4 (MRP4). In patients of EA with CKD (CRIC cohort), we found striking associations between uric acid and SNPs on ABCG2, a key transporter of uric acid by intestine. Compared with ABCG2, SLC2A9 played a much less significant role in this subset of patients with CKD. SNPs in other SLC (e.g. SLC22A8 or OAT3) and ABC (e.g. ABCC4 or MRP4) genes appear to make a weak gender-dependent contribution to uric acid homeostasis in CKD. As renal urate transport is affected in the setting of declining kidney function, extra-renal ABCG2 appears to play a compensatory role—a notion consistent with animal studies and the Remote Sensing and Signaling Hypothesis. Overall, the data indicate how different urate transporters become more or less important depending on renal function, ethnicity and gender. Therapies focused on enhancing ABCG2 urate handling may be helpful in the setting of CKD and hyperuricemia.