Miyazaki T, Ise M, Seo H, Niwa T
Nagoya University Daiko Medical Center, Japan.
Kidney Int Suppl. 1997 Nov;62:S15-22.
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.
我们最近报道，饮食中蛋白质代谢产物硫酸吲哚酚的血清水平在尿毒症大鼠和患者中均升高，并且给尿毒症大鼠注射硫酸吲哚酚会加速肾小球硬化的进程。因此，我们推测，诸如硫酸吲哚酚之类的蛋白质代谢产物在肾单位上的负荷过重会促进慢性肾衰竭（CRF）的进展。最近的研究表明，在各种肾脏疾病中，肾小管间质损伤在决定是否会发生进行性肾功能障碍方面与肾小球硬化同等重要或更为重要。在本研究中，为了阐明硫酸吲哚酚在CRF进展中的作用，我们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）-β1、金属蛋白酶组织抑制剂（TIMP-1）和前α1（I）型胶原。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-β1、TIMP-1和前α1（I）型胶原的mRNA水平，同时伴有肾功能显著下降和肾小球硬化加重。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，残余肾单位上蛋白质代谢产物硫酸吲哚酚的负荷过重与尿毒症肾脏中TGF-β1生物活性增加有关，这会增强TIMP-1和1型胶原的肾脏表达，导致CRF的进展。
