Indoxyl sulfate down-regulates SLCO4C1 transporter through up-regulation of GATA3

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. However, the precise mechanism of the nephrotoxicity of uremic toxins on renal transport has been poorly understood. Here we report that indoxyl sulfate, one of the potent uremic toxins, directly suppresses the renal-specific organic anion transporter SLCO4C1 expression through a transcription factor GATA3. The promoter region of SLCO4C1 gene has several GATA motifs, and indoxyl sulfate up-regulated GATA3 mRNA and subsequently down-regulated SLCO4C1 mRNA. Overexpression of GATA3 significantly reduced SLCO4C1 expression, and silencing of GATA3 increased SLCO4C1 expression vice versa. 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, following the reduction of plasma level of guanidinosuccinate. 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.