Perfluorooctane sulfonate induces autophagy-associated apoptosis through oxidative stress and the activation of extracellular signal–regulated kinases in renal tubular cells

Abstract

Perfluorooctane sulfonate (PFOS) is among the most abundant organic pollutants and is widely distributed in the environment, wildlife, and humans. Its toxic effects and biological hazards are associated with its long elimination half-life in humans. However, how it affects renal tubular cells (RTCs) remains unclear. In this study, PFOS was observed to mediate the increase in reactive oxygen species (ROS) generation, followed by the activation of the extracellular-signal-regulated kinase 1/2 (ERK1/2) pathway, which induced autophagy in RTCs. Although PFOS treatment induced autophagy after 6 h, prolonged treatment (24 h) reduced the autophagic flux by increasing lysosomal membrane permeability (LMP), leading to increased p62 protein accumulation and subsequent apoptosis. The increase in LMP was visualized through increased green fluorescence with acridine orange staining, and this was attenuated by 3-methyladenine, an autophagy inhibitor. N-acetyl cysteine and an inhibitor of the mitogen-activated protein kinase kinases (U0126) attenuated autophagy and apoptosis. Taken together, these results indicate that ROS activation and ROS-mediated phosphorylated ERK1/2 activation are essential to activate autophagy, resulting in the apoptosis of PFOS-treated RTCs. Our findings provide insight into the mechanism of PFOS-mediated renal toxicity.

l-Carnitine reduces reactive oxygen species/endoplasmic reticulum stress and maintains mitochondrial function during autophagy-mediated cell apoptosis in perfluorooctanesulfonate-treated renal tubular cells

“…We previously reported that 24-h prolonged PFOS treatment can block normal autophagic flux by increasing the accumulation of p62 and LC3BII 3 . Lysosome integrity was examined using an AO assay by assessing LMP (Fig.…”

“…We previously demonstrated that N-acetylcysteine (NAC), a ROS scavenger, rescues RTCs from PFOS-mediated apoptosis triggered by autophagy activation because the autophagy inhibition due to 3-methyladenine can block the aforementioned apoptosis 3 . Herein, we examined the mechanism underlying the protective effects of l -Carnitine on autophagy-associated apoptosis in the RTCs treated with PFOS.…”

“…We previously demonstrated that PFOS-induced ROS can result in the autophagy-associated apoptosis in RTCs, which can be suppressed by NAC (a ROS scavenger) through the suppression of PFOS-induced ERK1/2 phosphorylation. This suggests that the ERK pathway is a downstream effector of oxidative stress 3 . Herein, we extended our previous finding by demonstrating that PFOS induces autophagy-associated apoptosis in an ER-dependent manner.…”

“…For example, PFOS induces oxidative stress injury due to the suppression of antioxidative enzymes (including Gpx-1, SOD1, and catalase) both in vitro and in vivo 2 . In addition, PFOS induces autophagy-associated apoptosis through ROS-mediated ERK1/2 activation, which is followed by the blockade of the normal autophagic flux in RTCs 3 . In the present study, we extended our previous research by analyzing the protective effect of l -Carnitine on autophagy-associated apoptosis and its underlying molecular mechanisms.…”

“…In addition, PFOS can induce autophagy activation with increased Beclin and LC3BII expression through reactive oxygen species (ROS)-mediated extracellular signal–regulated kinase (ERK) activation, which is followed by impeded autophagic flux, increased lysosomal membrane permeability (LMP), and, consequently, RTC apoptosis. N-acetyl cysteine (a ROS scavenger) and U0126 (a mitogen-activated protein kinase [MAPK] inhibitor) can rescue PFOS-mediated autophagy activation and, consequently, autophagy-associated apoptosis in RTCs 3 .…”