Stimulating effect of indoxyl sulfate on progression of renal failure and development of an inhibitor of its production

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To clarify the role of indoxyl sulfate in the progression of renal failure, the expressions of genes related to tubulointerstitial fibrosis such as TGF-b1, TIMP-1 and pro al(I) collagen were examined in the renal cortex of 5/6-nephrectomized uremic rats given indoxyl sulfate. The administration of indoxyl sulfate for 5 weeks significantly increased the mRNA levels of transforming growth factor (TGF)-β1, tissue inhibitor of metalloproteinases (TIMP)-1 and pro al(I) collagen in the uremic rats given indoxyl sulfate compared with the control uremic rats, accompanied by a significant decline in renal function and worsening of glomerular sclerosis. Thus, we hypothesized that the overload of protein metabolites such as indoxyl sulfate on nephrons promotes the progression of CRF.Further, to clarify if indoxyl sulfate administration affects the expression of organic anion transporter (OAT)-1 and OAT3 in the kidneys, indoxyl sulfate was administered to 5/6-nephrectomized uremic rats for 16 weeks. Indoxyl sulfate was localized in the proximal tubular epithelial cells, especially of dilated tubules, of the control uremic rat kidneys, and that indoxyl sulfate administration markedly increased the tubular staining of indoxyl sulfate. The administration of indoxyl sulfate further dccreased the expression of OAT1 and increased the expression of OAT3. The immunostaining of indoxyl sulfate was more intense in the OAT3-positive proximal tubules rather than in the OAT1-positive proximal tubules. In conclusion, indoxyl sulfate is excreted to urine through active uptake by OAT1 and OAT3 in the basolateral membranes of renal proximal tubules. Uremic rats, especially indoxyl sulfate-administered uremic rats, showed decreased expression of OAT1 and increased expression of OAT3. The target of nephrotoxicity of indoxyl sulfate seems to te OAT3-expressed proximal tubules.