An oral sorbent reduces overload of indoxyl sulphate and gene expression of TGF-beta1 in uraemic rat kidneys.
BACKGROUND
An oral adsorbent (AST-120) delays the progression of chronic renal failure (CRF). The aims of the present study are to determine the effects of AST-120 on the localization of indoxyl sulphate in uraemic rat kidneys, and to examine whether AST-120 reduces the renal cortical gene expression of transforming growth factor (TGF)-beta1, tissue inhibitor of metalloproteinase (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 such that both rats in each pair exhibited almost the same levels of serum creatinine, 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 sulphate 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 creatinine, blood urea nitrogen and urinary protein as well as increased levels of creatinine clearance as compared with control uraemic rats. AST-120 markedly decreased indoxyl sulphate levels in both serum and urine. Immunohistochemistry demonstrated that indoxyl sulphate was localized in the renal proximal tubular epithelial cells, especially of dilated tubules, and that AST-120 markedly reduced the tubular staining of indoxyl sulphate. AST-120 attenuated 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 pro-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 proximal tubular epithelial cells.
Miyazaki
T
T
Nagoya University Daiko Medical Center, 1-1-20, Daiko-minami, Higashi-ku, Nagoya, Japan.
Aoyama
I
I
Ise
M
M
Seo
H
H
Niwa
T
T
D000327:Adsorption; D000818:Animals; D001806:Blood Urea Nitrogen; D002244:Carbon / Q000494:pharmacology*; D003404:Creatinine / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D007200:Indican / Q000032:analysis / Q000378:metabolism*; D008297:Male; D009392:Nephrectomy; D010087:Oxides / Q000494:pharmacology*; D011347:Procollagen / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000235:genetics*; D014511:Uremia / Q000235:genetics / Q000503:physiopathology*
D010087:Oxides; D011347:Procollagen; D019715:Tissue Inhibitor of Metalloproteinase-1; D016212:Transforming Growth Factor beta; D002244:Carbon; C040896:AST 120; D003404:Creatinine; D007200:Indican