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

Shimizu H, Bolati D, Adijiang A, Enomoto A, Nishijima F, Dateki M, Niwa T. Senescence and dysfunction of proximal tubular cells are associated with activated p53 expression by indoxyl sulfate. Am J Physiol Cell Physiol 299: C1110-C1117, 2010. First published August 18, 2010; doi:10.1152/ajpcell.00217.2010.-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 beta-galactosidase, a marker of cellular senescence, and the expression of alpha-smooth muscle actin (alpha-SMA), a marker of fibrosis, through inducing p53 expression and phosphorylation. Pifithrin-alpha, 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 alpha-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 beta-galactosidase, p53 and alpha-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.