Indoxyl sulfate stimulates renal synthesis of transforming growth factor-beta 1 and progression of renal failure

Kidney Int Suppl. 1997 Dec;63:S211-4.

Abstract

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.

MeSH terms

  • Animals
  • Cells, Cultured
  • Disease Progression
  • Enzyme-Linked Immunosorbent Assay
  • Gene Expression Regulation / drug effects
  • Indican / pharmacology*
  • Intercellular Adhesion Molecule-1 / biosynthesis
  • Intercellular Adhesion Molecule-1 / genetics
  • Kidney / drug effects
  • Kidney / metabolism*
  • Kidney / pathology
  • Kidney Failure, Chronic / pathology*
  • RNA, Messenger / biosynthesis
  • Rats
  • Swine
  • Transforming Growth Factor beta / biosynthesis*

Substances

  • RNA, Messenger
  • Transforming Growth Factor beta
  • Intercellular Adhesion Molecule-1
  • Indican