一种口服吸附剂可减轻尿毒症大鼠肾脏中硫酸吲哚酚的负荷及转化生长因子β1的基因表达。

An oral sorbent reduces overload of indoxyl sulphate and gene expression of TGF-beta1 in uraemic rat kidneys.

作者信息

Miyazaki T, Aoyama I, Ise M, Seo H, Niwa T

机构信息

Nagoya University Daiko Medical Center, 1-1-20, Daiko-minami, Higashi-ku, Nagoya, Japan.

出版信息

Nephrol Dial Transplant. 2000 Nov;15(11):1773-81. doi: 10.1093/ndt/15.11.1773.

DOI:10.1093/ndt/15.11.1773

PMID:11071964

Abstract

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.

摘要

背景

口服吸附剂（AST - 120）可延缓慢性肾衰竭（CRF）的进展。本研究旨在确定AST - 120对尿毒症大鼠肾脏中硫酸吲哚酚定位的影响，并研究AST - 120是否能降低转化生长因子（TGF）-β1、金属蛋白酶组织抑制剂（TIMP）-1和前α1（I）型胶原在肾皮质的基因表达，以及改善尿毒症大鼠的肾小球和肾小管间质损伤。

方法

5/6肾切除术后两周，将10只大鼠配对，使每对大鼠的血清肌酐、血尿素氮和肌酐清除率水平几乎相同。每对中的一只大鼠被分配到对照尿毒症组，另一只被分配到每天接受AST - 120治疗11周的尿毒症组。使用我们开发的单克隆抗硫酸吲哚酚抗体，通过免疫组织化学研究硫酸吲哚酚的定位。使用Northern印迹法研究肾皮质基因表达。

结果

与对照尿毒症大鼠相比，接受AST - 120治疗的大鼠血清肌酐、血尿素氮和尿蛋白水平降低，肌酐清除率升高。AST - 120显著降低了血清和尿液中的硫酸吲哚酚水平。免疫组织化学显示，硫酸吲哚酚定位于肾近端肾小管上皮细胞，尤其是扩张的肾小管，并且AST - 120显著减少了硫酸吲哚酚的肾小管染色。AST - 120减轻了间质纤维化、肾小管损伤以及肾小球硬化，并降低了TGF -β1、TIMP -1和前α1（I）型胶原的肾基因表达。