INDOXYL SULFATE STIMULATES RENAL SYNTHESIS OF TRANSFORMING GROWTH-FACTOR-BETA-1 AND PROGRESSION OF RENAL-FAILURE

We recently demonstrated that the administration of indoxyl sulfate (d ietary protein metabolite) to 5/6-nephrectomized rats accelerated the progression of chronic renal failure by increasing the transforming gr owth factor (TGF)-beta 1 synthesis in the kidneys, which enhanced the renal expressions of tissue inhibitor of metalloproteinase (TIMP)-1 an d type 1 collagen, leading to renal fibrosis. The aim of the present s tudy was to clarify the mechanism by which the administration of indox yl sulfate increases TGF-beta 1 in the kidneys of uremic rats. Since i nfiltrative monocytes are suggested to be an important source of TGF-b eta 1 in tubulointerstitial fibrosis, we examined the effect of indoxy l sulfate administration to uremic rats on the renal gene expression o f intercellular adhesion molecule (ICAM)-1, which is involved in the i nfiltration of monocytes to kidneys. Indoxyl sulfate administration wa s observed to enhance the mRNA levels of ICAM-1 as well as those of TG F-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 th at the addition of indoxyl sulfate significantly increased the synthes is of TGF-beta 1 in cultured proximal tubular cells. Thus, the overloa d of indoxyl sulfate in uremic kidneys increased the infiltration of m onocytes and directly increased the synthesis of TGF-beta 1 in proxima l tubular cells.