INDOXYL SULFATE INCREASES THE GENE EXPRESSIONS OF TGF-BETA-1, TIMP-1 AND PRO-ALPHA-1(I) COLLAGEN IN UREMIC RAT KIDNEYS

We recently reported that the serum levels of indoxyl sulfate, a dieta ry protein metabolite, are increased in both uremic rats and patients, and that the administration of indoxyl sulfate to uremic rats acceler ates the progression of glomerular sclerosis. Thus, we hypothesize tha t the overload of protein metabolites such as indoxyl sulfate on nephr ons promotes the progression of chronic renal failure (CRF). Recent st udies revealed that tubulointerstitial injury is of equal or greater i mportance than glomerular sclerosis in determining whether progressive renal dysfunction will ensue in various renal diseases. In the presen t study, to clarify the role of indoxyl sulfate in the progression of CRF, the expressions of genes related to tubulointerstitial fibrosis s uch as transforming growth factor (TGF)-beta 1, tissue inhibitor of me talloproteinases (TIMP-1) and pro-alpha 1(I) collagen were examined in the renal cortex of 5/6-nephrectomized uremic rats given indoxyl sulf ate. In the first experiment, the administration of indoxyl sulfate fo r five weeks significantly increased the mRNA levels of TGF-beta 1, TI MP-1 and pro-alpha 1(I) collagen in the uremic rats given indoxyl sulf ate compared with the control uremic rats, accompanied by a significan t decline in renal function and worsening of glomerular sclerosis. In the second experiment, the administration of indoxyl sulfate for 2.5 w eeks also increased the expression of the mRNA levels with no signific ant decline in the renal function. In conclusion, these findings indic ate that the overload of the protein metabolite indoxyl sulfate on rem nant nephrons is involved in the increased bioactivity of TGF-beta 1 i n uremic kidneys, which enhances the renal expression of TIMP-1 and ty pe 1 collagen, leading to the progression of CRF.