Gut-derived uremic toxin handling in vivo requires OAT-mediated tubular secretion in chronic kidney disease
Gut-derived uremic toxin handling in vivo requires OAT-mediated tubular secretion in chronic kidney disease
复制标题
DOI：
10.1172/jci.insight.133817
复制
发表时间：
2020-04-09
期刊：
影响因子：
8
通讯作者：
Nigam, Sanjay K.
中科院分区：
文献类型：
--
作者：
Bush, Kevin T.;Singh, Prabhleen;Nigam, Sanjay K.
肾脏有机阴离子转运体OAT1(也被称为SLC22A6，最初被确定为NKT)和OAT3(也被称为SLC22A8)在慢性肾脏疾病(CKD)中的作用尚不清楚。尤其是从残存近端小管分泌物的观点来看，这是处理CKD蛋白结合尿毒症毒素的关键适应机制。采用肾大部切除术(STN)模型，观察OAT抑制剂丙磺舒对STN大鼠血浆代谢产物的影响。与Oat1-KO和OAT3-KO小鼠的代谢组学数据进行比较，支持燕麦在尿毒症溶质残留管状分泌中的中心地位，如吲哚硫酸盐、雷尼酸和邻氨基苯甲酸酯。我们的数据与已发表的关于肠道微生物衍生的尿毒症溶质的代谢组学数据重叠-这可能在信号和毒性中具有双重作用-表明燕麦在决定其在CKD中的血浆水平方面发挥了关键作用。因此，燕麦与其他SLC和ABC药物转运体一起，对于尿毒症溶质跨组织和进入各种体液的移动至关重要，这与遥感和信号理论一致。这些数据支持燕麦在调节远程组织间和器官间通讯(肠道微生物区系-血液-肝脏-肾脏-尿液)中的作用。这一结果也对理解涉及尿毒症毒素的药物-代谢物相互作用具有重要意义。
The role of the renal organic anion transporters OAT1 (also known as SLC22A6, originally identified as NKT) and OAT3 (also known as SLC22A8) in chronic kidney disease (CKD) remains poorly understood. This is particularly so from the viewpoint of residual proximal tubular secretion, a key adaptive mechanism to deal with protein-bound uremic toxins in CKD. Using the subtotal nephrectomy (STN) model, plasma metabolites accumulating in STN rats treated with and without the OAT inhibitor, probenecid, were identified. Comparisons with metabolomics data from Oat1-KO and Oat3-KO mice support the centrality of the OATs in residual tubular secretion of uremic solutes, such as indoxyl sulfate, kynu renate, and anthranilate. Overlapping our data with those of published metabolomics data regarding gut microbiome-derived uremic solutes - which can have dual roles in signaling and toxicity - indicates that OATs play a critical role in determining their plasma levels in CKD Thus, the OATs, along with other SLC and ABC drug transporters, are critical to the movement of uremic solutes across tissues and into various body fluids, consistent with the remote sensing and signaling theory. The data support a role for OATs in modulating remote interorganismal and interorgan communication (gut microbiota-blood-liver-kidney-urine). The results also have implications for understanding drug-metabolite interactions involving uremic toxins.