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 (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.
Miyazaki
T
T
Nagoya University Daiko Medical Center, Japan.
Ise
M
M
Hirata
M
M
Endo
K
K
Ito
Y
Y
Seo
H
H
Niwa
T
T
D000818:Animals; D002478:Cells, Cultured; D018450:Disease Progression; D004797:Enzyme-Linked Immunosorbent Assay; D005786:Gene Expression Regulation / Q000187:drug effects; D007200:Indican / Q000494:pharmacology*; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis / Q000235:genetics; D007668:Kidney / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D007676:Kidney Failure, Chronic / Q000473:pathology*; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D013552:Swine; D016212:Transforming Growth Factor beta / Q000096:biosynthesis*
D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D018799:Intercellular Adhesion Molecule-1; D007200:Indican