Senescence and dysfunction of proximal tubular cells are associated with activated p53 expression by indoxyl sulfate

American Journal of Physiology - Cell Physiology - Tập 299 Số 5 - Trang C1110-C1117 - 2010
Hidehisa Shimizu1, Dilinaer Bolati2, Ayinuer Adijiang2, Atsushi Enomoto3, Fuyuhiko Nishijima4, Minori Dateki5, Toshimitsu Niwa2
1Department of Advanced Medicine for Uremia, Nagoya University Graduate School of Medicine, Nagoya, Japan
2Department of Advanced Medicine for Uremia, Nagoya University Graduate School of Medicine, and
3Institute for Advanced Research, Nagoya University, Nagoya;
4Biomedical Research Laboratories, Kureha Company, Tokyo; and
5Graduate School of Science, Toho University, Funabashi, Japan

Tóm tắt

Various uremic toxins accumulate in patients with chronic renal failure (CRF) and one of them is indoxyl sulfate, which accelerates the progression of CRF through unknown mechanisms. The present study investigates how indoxyl sulfate promotes CRF using the proximal tubular cell line HK-2 and CRF rats. Indoxyl sulfate inhibited serum-induced cell proliferation and promoted the activation of senescence-associated β-galactosidase, a marker of cellular senescence, and the expression of α-smooth muscle actin (α-SMA), a marker of fibrosis, through inducing p53 expression and phosphorylation. Pifithrin-α, p-nitro, a p53 inhibitor, blocked these effects. Indoxyl sulfate evoked reactive oxygen species (ROS), and the antioxidant N-acetylcysteine inhibited indoxyl sulfate-induced p53 expression and phosphorylation, as well as indoxyl sulfate-induced α-SMA expression. We previously demonstrated that although cellular senescence and fibrosis are detectable in the kidneys of CRF rats, the oral adsorbent AST-120 repressed these effects. Here, we found that β-galactosidase, p53 and α-SMA were expressed and colocalized in the renal tubules of CRF rats, whereas AST-120 decreased the expression of these genes. Taken together, these findings indicate that indoxyl sulfate induces the expression and phosphorylation of p53 though ROS production, thus inhibiting cell proliferation and promoting cellular senescence and renal fibrosis.

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Thông tin
Thông tin xuất bản

American Journal of Physiology - Cell Physiology

Tập 299 Số 5

C1110-C1117

Thông tin tác giả