Blockade of renal malignant cycle by transcriptional regulation of SLCO transporter

尿毒症毒素的积聚抑制了各种肾脏转运蛋白的表达，这种抑制可能会进一步降低肾功能，从而导致尿毒症毒素的积聚。吲哚硫酸盐是一种有效的尿毒症毒素，它通过转录因子GATA3直接抑制肾脏特异的有机阴离子转运体SLCO4c1的表达。在这种情况下，大鼠给药后slco4c1的肾脏表达减少，在这种情况下，slco4c1的首选底物之一琥珀酸胍的血浆水平显著增加，而不改变血浆肌酐。此外，在5/6肾切除大鼠中，口服吸附剂AST-120显著降低了血浆硫酸吲哚含量，反之则增加了slco4c1的表达。这些数据表明，清除吲哚硫酸盐并阻断其信号通路可能有助于恢复SLCO4C1介导的尿毒症毒素在CKD中的排泄。

The accumulated uremic toxins inhibit the expression of various renal transporters and this inhibition may further reduce renal function and subsequently cause the accumulation of uremic toxins. Indoxyl sulfate, one of the potent uremic toxins, directly suppresses the renal-specific organic anion transporter SLCO4C1 expression through a transcription factor GATA3.Administration of indoxyl sulfate in rats reduced renal expression of slco4c1 and under this condition, plasma level of guanidinosuccinate, one of the preferable substrates of slco4c1, was significantly increased without changing plasma creatinine. Furthermore, in 5/6 nephrectomized rats, treatment with oral adsorbent AST-120 significantly decreased plasma indoxyl sulfate level and conversely increased the expression of slco4c1. These data suggest that the removal of indoxyl sulfate and blocking its signal pathway may help to restore the SLCO4C1-mediated renal excretion of uremic toxins in CKD.