utionarily conserved transcriptional regulators that play critical roles in development, differentiation and cell proliferation. However, the physiological and pathophysiological roles of GATA factors in adult tissues, especially in the kidney, have been poorly understood. In this study, we revealed that the altered expression of GATA factor by IS is involved in the pathophysiology of CKD. It has been reported that NG-monomethy-L-arginine, an endogenous inhibitor of nitric oxide synthase, inhibited EPO gene expression by both increasing GATA2 mRNA expression and GATA binding activity. However, L-NMMA was not accumulated in CKD patients and not considered as a uremic toxin. Thus, our data clearly showed that uremic toxins affect the expression of GATA factor. IS is one of the most representative uremic toxins. So far, various toxic effects of IS have been reported, such as endothelial dysfunction, induction of oxidative stress, upregulation of ICAM-1 and MCP-1, induction of TGF-b1 and NF-kB. Our data suggests the further importance of IS as a therapeutic target for CKD patients. In addition, it has been reported that IS also Elesclomol inhibit transport activity of some transporters such as MRP4 and BCRP . Our data showed that IS can inhibit transporters transcriptionally as well as functionally. However, the mechanism that IS increased the expression of GATA factors and the effects of dysregulation of GATA factors in other organs remain unknown. Further study is needed to clearly define the pathological role of IS and GATA factors in CKD. IS is a protein-bound uremic toxin. It has been reported that the mean concentrations of total and free IS in uremic populations were 23.1 mg/L and 3.22 mg/L, respectively, which suggests that the protein-bound IS fraction was over 80% in . These data clearly suggest that SLCO4C1 was negatively regulated transcriptionally by GATA3. IS decreases slco4c1 transport activity Based on these results, we next examined the relation of slco4c1 expression level and its function by administration of IS. After 4 weeks administration of IS, the plasma IS level was significantly increased compared with the control group , and the renal protein level of slco4c1 was significantly decreased. Immunohistochemical analysis also 12023528 revealed that the immunostaining of slco4c1 was reduced in IS-treated kidney compared with control. Under this condition, plasma 26243621 GSA concentration was significantly increased, although plasma creatinine was not changed. These data suggested that IS decreases renal slco4c1 expression, which may reduce the excretion of uremic toxin without change of glomerular function. Under the condition, plasma concentrations of ADMA and trans-aconinate were not changed. Removal of IS increased slco4c1 expression in CKD model Clinically, oral adsorbent AST-120 has been used to remove serum IS. To elucidate whether lowering the plasma IS concentration in CKD increases renal slco4c1 expression in vivo, oral adsorbent AST-120 was administered to subtotal nephrectomized renal failure rats. In 5/6 Nx rats, the plasma level of IS was significantly higher compared with sham-operated group. In addition, the plasma IS concentration in AST-120-administered group was significantly decreased compared with that in sham-operated and control groups. The renal slco4c1 mRNA Indoxyl Sulfate Downregulates SLCO4C1 through GATA CKD patients. In our experiments, free IS fraction in the albumincontaining medium was about 30% and about 70% of IS wa