Stat3 contributes to indoxyl sulfate-induced inflammatory and fibrotic gene expression and cellular senescence.
OBJECTIVE
Increased phosphorylation (activation) of signal transducer and activator of transcription 3 (Stat3) on tyrosine 705 leads to renal fibrosis. Indoxyl sulfate, a uremic toxin, induces renal fibrosis through expression of transforming growth factor-β(1) (TGF-β(1)) in proximal tubular cells. The present study aimed to determine whether Stat3 is involved in indoxyl sulfate-induced dysfunction of proximal tubular cells.


METHODS
Localization of phosphorylated Stat3 in the kidneys of normal, subtotally nephrectomized, and AST-120-treated subtotally nephrectomized rats was examined by immunohistochemistry. The effect of indoxyl sulfate on phosphorylation of Stat3 and the role of Stat3 on indoxyl sulfate-induced cellular effects were examined using human proximal tubular cells (HK-2 cells).


RESULTS
Subtotally nephrectomized rats showed increased immunostaining of phosphorylated Stat3 in the renal tubules compared with normal rats. Administration of AST-120, which reduces serum level of indoxyl sulfate, to subtotally nephrectomized rats reduced the immunostaining of phosphorylated Stat3 in the renal tubules. Indoxyl sulfate induced phosphorylation of Stat3 in HK-2 cells. Stat3 small interfering RNA suppressed indoxyl sulfate-induced expression of an inflammation marker gene (monocyte chemotactic protein-1), fibrosis marker genes (TGF-β(1), α-smooth muscle actin) and a subunit of nuclear factor-ĸB (p65), and attenuated a cellular senescence marker, senescence-associated β-galactosidase activity.


CONCLUSIONS
Stat3 is involved in indoxyl sulfate-induced inflammatory and fibrotic gene expression and cellular senescence in proximal tubular cells.
Department of Advanced Medicine for Uremia, Nagoya University School of Medicine, Nagoya, Japan.
Hidehisa
H
Shimizu
Maimaiti
M
Yisireyili
Fuyuhiko
F
Nishijima
Toshimitsu
T
Niwa
D058186:Acute Kidney Injury / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D000818:Animals; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000502:physiology*; D004195:Disease Models, Animal; D005355:Fibrosis / Q000235:genetics / Q000276:immunology / Q000473:pathology; D015870:Gene Expression / Q000276:immunology; D006801:Humans; D007200:Indican / Q000378:metabolism*; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000276:immunology; D008297:Male; D009392:Nephrectomy; D010766:Phosphorylation / Q000502:physiology; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D050796:STAT3 Transcription Factor / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D014511:Uremia / Q000235:genetics / Q000276:immunology / Q000473:pathology
D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor; C494088:Stat3 protein, rat; D007200:Indican