An oral sorbent reduces overload of indoxyl sulphate and gene expression of TGF-beta 1 in uraemic rat kidneys

Background. An oral adsorbent (AST-120) delays the progression of chronic r enal failure (CRF). The aims of the present study are to determine the effe cts of AST-120 on the localization of indoxyl sulphate in uraemic rat kidne ys, and to examine whether AST-120 reduces the renal cortical gene expressi on of transforming growth factor (TGF)-beta1, tissue inhibitor of metallopr oteinase (TIMP)-1 and pro-alpha1(I)collagen, and ameliorates glomerular and tubulointerstitial injuries in uraemic rats. Methods. Two weeks after 5/6-nephrectomy, 10 rats were divided into pairs s uch that both rats in each pair exhibited almost the same levels of serum c reatinine, blood urea nitrogen and creatinine clearance. One rat from each pair was assigned to a control uraemic group, the other to a uraemic group which received AST-120 everyday for 11 weeks. The localization of indoxyl s ulphate was studied by immunohistochemistry using a monoclonal anti-indoxyl sulphate antibody we had developed. The renal cortical gene expression was studied by using northern blotting. Results. Rats treated with AST-120 showed decreased levels of serum creatin ine, blood urea nitrogen and urinary protein as well as increased levels of creatinine clearance as compared with control uraemic rats. AST-120 marked ly decreased indoxyl sulphate levels in both serum and urine. Immunohistoch emistry demonstrated that indoxyl sulphate was localized in the renal proxi mal tubular epithelial cells, especially of dilated tubules, and that AST-1 20 markedly reduced the tubular staining of indoxyl sulphate. AST-120 atten uated interstitial fibrosis, tubular injury as well as glomerular sclerosis , and reduced the renal gene expression of TGF-beta1, TIMP-1 and pro-alpha1 (I)collagen. Conclusions. AST-120 reduces the gene expression of TGF-beta1, TIMP-1 and p ro-alpha1(I)collagen in the kidneys, and delays the progression of CRF, at least in part, by alleviating the overload of indoxyl sulphate on remnant p roximal tubular epithelial cells.