Indoxyl sulfate increases the gene expressions of TGF-beta 1, TIMP-1 and pro-alpha 1(I) collagen in uremic rat kidneys.
Indoxyl sulfate increases the gene expressions of TGF-beta 1, TIMP-1 and pro-alpha 1(I) collagen in uremic rat kidneys.
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Indoxylsulfate 可增加尿毒症大鼠肾脏中 TGF-β1、TIMP-1 和 pro-α1(I) 胶原蛋白的基因表达。
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发表时间：
1997
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影响因子：
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通讯作者：
T. Niwa
中科院分区：
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作者：
T. Miyazaki;M. Ise;H. Seo;T. Niwa
我们最近报道，硫酸吲哚酚，膳食蛋白质代谢产物，血清中的水平增加，在尿毒症大鼠和患者，并表示硫酸吲哚酚管理尿毒症大鼠加速肾小球硬化的进展。因此，我们假设蛋白质代谢物如硫酸吲哚酚在肾单位上的过载促进慢性肾功能衰竭（CRF）的进展。近年来的研究表明，在各种肾脏疾病中，肾小管间质损伤在决定进行性肾功能不全是否会发生方面与肾小球硬化同等或更重要。为了阐明硫酸吲哚酚在慢性肾衰进展中的作用，本研究检测了给予硫酸吲哚酚的5/6肾切除尿毒症大鼠肾皮质中与肾小管间质纤维化相关的基因表达，如转化生长因子（TGF）-β 1、金属蛋白酶组织抑制剂（TIMP-1）和前α 1（I）胶原。在第一个实验中，与对照尿毒症大鼠相比，给予硫酸吲哚酚5周显著增加了给予硫酸吲哚酚的尿毒症大鼠中TGF-β 1、TIMP-1和pro-alpha 1（I）胶原的mRNA水平，伴随着肾功能的显著下降和肾小球硬化的恶化。在第二个实验中，给予硫酸吲哚酚2.5周也增加了mRNA水平的表达，而肾功能没有显著下降。总之，这些发现表明，蛋白代谢产物硫酸吲哚酚在残余肾单位上的过载参与了尿毒症肾脏中TGF-β 1的生物活性增加，其增强了肾脏TIMP-1和1型胶原的表达，导致CRF的进展。
We recently reported that the serum levels of indoxyl sulfate, a dietary protein metabolite, are increased in both uremic rats and patients, and that the administration of indoxyl sulfate to uremic rats accelerates the progression of glomerular sclerosis. Thus, we hypothesize that the overload of protein metabolites such as indoxyl sulfate on nephrons promotes the progression of chronic renal failure (CRF). Recent studies revealed that tubulointerstitial injury is of equal or greater importance than glomerular sclerosis in determining whether progressive renal dysfunction will ensue in various renal diseases. In the present study, to clarify the role of indoxyl sulfate in the progression of CRF, the expressions of genes related to tubulointerstitial fibrosis such as transforming growth factor (TGF)-beta 1, tissue inhibitor of metalloproteinases (TIMP-1) and pro-alpha 1(I) collagen were examined in the renal cortex of 5/6-nephrectomized uremic rats given indoxyl sulfate. In the first experiment, the administration of indoxyl sulfate for five weeks significantly increased the mRNA levels of TGF-beta 1, TIMP-1 and pro-alpha 1(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. In the second experiment, the administration of indoxyl sulfate for 2.5 weeks also increased the expression of the mRNA levels with no significant decline in the renal function. In conclusion, these findings indicate that the overload of the protein metabolite indoxyl sulfate on remnant nephrons is involved in the increased bioactivity of TGF-beta 1 in uremic kidneys, which enhances the renal expression of TIMP-1 and type 1 collagen, leading to the progression of CRF.