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Am J Nephrol. 2013;37(2):97-103. doi: 10.1159/000346420. Epub 2013 Jan 25.

Indoxyl sulfate enhances p53-TGF-β1-Smad3 pathway in proximal tubular cells.

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Department of Advanced Medicine for Uremia, Nagoya University Graduate School of Medicine, Nagoya, Japan.



Indoxyl sulfate-induced activation of nuclear factor (NF)-ĸB promotes transforming growth factor (TGF)-β1 in human proximal tubular cells (HK-2 cells). The present study aimed to elucidate the cross talk among indoxyl sulfate, p53 and TGF-β1-Smad3 signaling in proximal tubular cells.


The effects of indoxyl sulfate on the expression of TGF-β1, Smad3, and α-smooth muscle actin (α-SMA) were determined using HK-2 cells. As for in vivo experiments the following animals were used: Dahl salt-resistant normotensive rats (DN) and indoxyl sulfate-administered Dahl salt-resistant normotensive rats (DN+IS).


Both indoxyl sulfate and nutlin-3, a specific p53 inducer, stimulated TGF-β1 expression, which was suppressed by pifithrin-α, p-nitro, a p53 inhibitor. Further, indoxyl sulfate stimulated TGF-β1-induced expression of α-SMA by enhancing Smad3 expression and TGF-β1-induced Smad3 phosphorylation. Indoxyl sulfate induced phosphorylation of extracellular signal-regulated kinase (ERK). U0126, an inhibitor of ERK pathway, prevented indoxyl sulfate-induced upregulation of Smad3 expression. Immunohistochemistry demonstrated that TGF-β1 and Smad3 were localized in renal tubular cells, and that indoxyl sulfate increased the TGF-β1 and Smad3-positive area in the kidney.


Indoxyl sulfate stimulates p53-induced TGF-β1 expression and TGF-β1-induced α-SMA expression in proximal tubular cells. Indoxyl sulfate-induced Smad3 accelerates TGF-β1-induced α-SMA expression through ERK activation. Thus, indoxyl sulfate enhances p53-TGF-β1-Smad3 pathway in proximal tubular cells.

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