Cadmium exposure induces rat proximal tubular cells injury via p62-dependent Nrf2 nucleus translocation mediated activation of AMPK/AKT/mTOR pathway.
Nuclear factor erythroid 2-related factor 2 (Nrf2) is a nuclear transcription factor of great concern which is widely involved in physiological and pathological processes of the organism, but the role and regulatory mechanism of Nrf2 in kidney exposed to cadmium (Cd) remain largely unknown. Here we demonstrated that Cd exposure induced injury in primary rat proximal tubular (rPT) cells and NRK-52E cell line, which was accompanied by autophagic flux blockade and subsequent accumulation of p62. Cd-activated nucleus translocation of Nrf2 depended on p62, which promoted antioxidant genes transcription, but it failed to against Cd-induced cell injury and ultimately succumbed to Cd toxicity. CDDO Methyl Ester (CDDO-ME) or ML385 treatment aggravated or alleviated rPT cells injury induced by Cd respectively, indicating that Nrf2 nucleus translocation played a negative role during Cd-induced rPT cells injury. Phosphorylation of 5' AMP-activated protein kinase (AMPK) decreased together with enhanced Nrf2 nucleus translocation in rPT cells exposed to Cd. Dephosphorylation of AMPK induced by Cd were facilitated or restored by CDDO-ME or ML385 treatment, which confirmed AMPK is a downstream factor of Nrf2. Simultaneously, CDDO-ME further enhanced Phosphorylation of mTOR and AKT which increased during Cd exposure. While, Cd-induced phosphorylation of mTOR and AKT were reversed by ML385 treatment. These results illustrated that Cd mediated Nrf2 nucleus translocation depends on p62 accumulation which results from autophagic flux inhibition. The enhanced nucleus translocation of Nrf2 suppresses phosphorylation of AMPK to inactivate AKT/mTOR signaling, and results in rPT cells injury finally.
['Dong|Wenxuan|W|', 'Liu|Gang|G|', 'Zhang|Kanglei|K|', 'Tan|Yun|Y|', 'Zou|Hui|H|', 'Yuan|Yan|Y|', 'Gu|Jianhong|J|', 'Song|Ruilong|R|', 'Zhu|Jiaqiao|J|', 'Liu|Zongping|Z|']
D055372:AMP-Activated Protein Kinases D000818:Animals D000975:Antioxidants D001343:Autophagy D002104:Cadmium D002467:Cell Nucleus D004785:Environmental Pollutants D005786:Gene Expression Regulation D007687:Kidney Tubules, Proximal D051267:NF-E2-Related Factor 2 D018384:Oxidative Stress D010766:Phosphorylation D051057:Proto-Oncogene Proteins c-akt D051381:Rats D015398:Signal Transduction D058570:TOR Serine-Threonine Kinases
Cadmium Nrf2 Kidney Autophagy Oxidative stress