Hypouricemic agents reduce indoxyl sulfate excretion by inhibiting the renal transporters OAT1/3 and ABCG2.
Hypouricemic agents reduce indoxyl sulfate excretion by inhibiting the renal transporters OAT1/3 and ABCG2.
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降尿酸药通过抑制肾脏转运蛋白 OAT1/3 和 ABCG2 来减少硫酸吲哚酚的排泄。
DOI：
10.1038/s41598-021-86662-9
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发表时间：
2021-03-31
影响因子：
4.6
通讯作者：
Iwanaga T
中科院分区：
文献类型：
--
作者：
Taniguchi T;Omura K;Motoki K;Sakai M;Chikamatsu N;Ashizawa N;Takada T;Iwanaga T
硫酸吲哚酚（IS）在慢性肾病（CKD）中在体内蓄积。在肾近端小管中，IS排泄由OAT 1/3和ABCG 2介导。这些转运蛋白可被某些降尿酸药物抑制;丙磺舒和苯溴马隆可抑制OAT，非布司他和苯溴马隆可抑制ABCG 2。因此，我们评估了包括dotinurad（一种对OAT或ABCG 2影响最小的新型选择性尿酸盐重吸收抑制剂）在内的降尿酸药物是否影响大鼠的IS清除率。完整的和腺嘌呤诱导的急性肾功能衰竭大鼠口服低尿酸血症药物，内源性IS和外源性稳定同位素标记的d4-IS在血浆和肾脏进行了测量。我们的研究结果表明，OAT抑制剂，如丙磺舒，抑制IS摄取到肾脏，导致血浆IS浓度增加，而ABCG 2抑制剂，如非布司他，通过抑制其在完整大鼠中的排泄，导致肾脏IS显著蓄积。这些药物的作用在腺嘌呤诱导的急性肾衰竭大鼠中降低，可能是由于肾脏OAT 1/3和ABCG 2表达的大幅降低。Dotinurad在两种条件下均未显著影响IS的清除。因此，我们认为不影响OAT和ABCG 2的降尿酸药物是治疗高尿酸血症并发CKD的有效治疗选择。
Indoxyl sulfate (IS) accumulates in the body in chronic kidney disease (CKD). In the renal proximal tubules, IS excretion is mediated by OAT1/3 and ABCG2. These transporters are inhibited by some hypouricemic agents; OATs by probenecid and benzbromarone, ABCG2 by febuxostat and benzbromarone. Thus, we evaluated whether hypouricemic agents including dotinurad, a novel selective urate reabsorption inhibitor with minimal effect on OATs or ABCG2, affect IS clearance in rats. Intact and adenine-induced acute renal failure rats were orally administered hypouricemic agents, and both endogenous IS and exogenously administered stable isotope-labeled d4-IS in the plasma and kidney were measured. Our results demonstrated that OATs inhibitors, such as probenecid, suppress IS uptake into the kidney, leading to increased plasma IS concentration, whereas ABCG2 inhibitors, such as febuxostat, cause renal IS accumulation remarkably by suppressing its excretion in intact rats. The effects of these agents were reduced in adenine-induced acute renal failure rats, presumably due to substantial decrease in renal OAT1/3 and ABCG2 expression. Dotinurad did not significantly affected the clearance of IS under both conditions. Therefore, we suggest that hypouricemic agents that do not affect OATs and ABCG2 are effective therapeutic options for the treatment of hyperuricemia complicated by CKD.
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DOI：
10.1111/cts.12809
发表时间：
2020-11
期刊：
Clinical and translational science
影响因子：
--
作者：
Lehtisalo M;Keskitalo JE;Tornio A;Lapatto-Reiniluoto O;Deng F;Jaatinen T;Viinamäki J;Neuvonen M;Backman JT;Niemi M
通讯作者：
Niemi M
DOI：
10.1152/ajprenal.1998.275.1.f154
发表时间：
1998-07-01
影响因子：
4.2
作者：
Stockelman, MG;Lorenz, JN;Stambrook, PJ
通讯作者：
Stambrook, PJ
影响因子：
19.6
作者：
Motojima, M;Hosokawa, A;Yoshioka, T
通讯作者：
Yoshioka, T
影响因子：
13.2
作者：
Iseki, K;Ikemiya, Y;Takishita, S
通讯作者：
Takishita, S
影响因子：
2.9
作者：
Schroeder, Jennifer C.;DiNatale, Brett C.;Murray, Iain A.;Flaveny, Colin A.;Liu, Qiang;Laurenzana, Elizabeth M.;Lin, Jyh Ming;Strom, Stephen C.;Omiecinski, Curtis J.;Amin, Shantu;Perdew, Gary H.
通讯作者：
Perdew, Gary H.