Miyazaki T, Ise M, Hirata M, Endo K, Ito Y, Seo H, Niwa T
Nagoya University Daiko Medical Center, Japan.
Kidney Int Suppl. 1997 Dec;63:S211-4.
We recently demonstrated that the administration of indoxyl sulfate (dietary protein metabolite) to 5/6-nephrectomized rats accelerated the progression of chronic renal failure by increasing the transforming growth factor (TGF)-beta 1 synthesis in the kidneys, which enhanced the renal expressions of tissue inhibitor of metalloproteinase (TIMP)-1 and type 1 collagen, leading to renal fibrosis. The aim of the present study was to clarify the mechanism by which the administration of indoxyl sulfate increases TGF-beta 1 in the kidneys of uremic rats. Since infiltrative monocytes are suggested to be an important source of TGF-beta 1 in tubulointerstitial fibrosis, we examined the effect of indoxyl sulfate administration to uremic rats on the renal gene expression of intercellular adhesion molecule (ICAM)-1, which is involved in the infiltration of monocytes to kidneys. Indoxyl sulfate administration was observed to enhance the mRNA levels of ICAM-1 as well as those of TGF-beta 1, TIMP-1 and pro alpha 1 (I) collagen in the renal cortex of 5/6-nephrectomized uremic rats. In addition, we demonstrated in vitro that the addition of indoxyl sulfate significantly increased the synthesis of TGF-beta 1 in cultured proximal tubular cells. Thus, the overload of indoxyl sulfate in uremic kidneys increased the infiltration of monocytes and directly increased the synthesis of TGF-beta 1 in proximal tubular cells.
我们最近证实，给5/6肾切除大鼠施用硫酸吲哚酚（膳食蛋白质代谢产物）可通过增加肾脏中转化生长因子（TGF）-β1的合成来加速慢性肾衰竭的进展，这增强了金属蛋白酶组织抑制剂（TIMP）-1和I型胶原的肾脏表达，导致肾纤维化。本研究的目的是阐明施用硫酸吲哚酚增加尿毒症大鼠肾脏中TGF-β1的机制。由于浸润性单核细胞被认为是肾小管间质纤维化中TGF-β1的重要来源，我们研究了给尿毒症大鼠施用硫酸吲哚酚对细胞间黏附分子（ICAM）-1肾脏基因表达的影响，ICAM-1参与单核细胞向肾脏的浸润。观察到给5/6肾切除的尿毒症大鼠施用硫酸吲哚酚可增强肾皮质中ICAM-1以及TGF-β1、TIMP-1和I型胶原α1前体（pro α1 (I) collagen）的mRNA水平。此外，我们在体外证明，添加硫酸吲哚酚可显著增加培养的近端肾小管细胞中TGF-β1的合成。因此，尿毒症肾脏中硫酸吲哚酚的过载增加了单核细胞的浸润，并直接增加了近端肾小管细胞中TGF-β1的合成。
