Abstract
Autophagy has an important renoprotective function and we recently found that autophagy inhibition is involved in cadmium (Cd)-induced nephrotoxicity. Here, we aimed to investigate the protective effect of trehalose (Tre), a novel autophagy activator, against Cd-induced cytotoxicity in primary rat proximal tubular (rPT) cells. First, data showed that Tre treatment significantly decreased Cd-induced apoptotic cell death of rPT cells via inhibiting caspase-dependent apoptotic pathway, evidenced by morphological analysis, flow cytometric and immunoblot assays. Also, administration with Tre protected rPT cells against Cd-induced lipid peroxidation. Inhibition of autophagic flux in Cd-exposed rPT cells was markedly restored by Tre administration, demonstrated by immunoblot analysis of autophagy marker proteins and GFP and RFP tandemly tagged LC3 method. Resultantly, Cd-induced autophagosome accumulation was obviously alleviated by Tre treatment. Meanwhile, blockage of autophagosome–lysosome fusion by Cd exposure was noticeably restored by Tre, which promoted the autophagic degradation in Cd-exposed rPT cells. Moreover, Tre treatment markedly recovered Cd-induced lysosomal alkalinization and impairment of lysosomal degradation capacity in rPT cells, demonstrating that Tre has the ability to restore Cd-impaired lysosomal function. Collectively, these findings demonstrate that Tre treatment alleviates Cd-induced cytotoxicity in rPT cells by inhibiting apoptosis and restoring autophagic flux.
Highlights
Cadmium (Cd) is a widespread environmental toxicant of increasing importance because of its extensive use in various anthropogenic and industrial activities.[1]
Our research group recently found that Cd exposure inhibits the autophagic flux in rat proximal tubular (rPT) cells, which has a negative impact on Cd nephrotoxicity.[14,15]
Morphological analysis by phase contrast microscopy showed decreased cell density, cellular detachment, shrunk and round morphology in Cd-treated cells. Such morphologic changes were significantly improved in 2.5 μM Cd plus 5 mM Tre group, demonstrating the significant protective effect of Tre on Cd-induced cytotoxicity in rPT cells
Summary
Cadmium (Cd) is a widespread environmental toxicant of increasing importance because of its extensive use in various anthropogenic and industrial activities.[1]. Trehalose (Tre), a natural occurring-linked disaccharide widely distributed in non-mammalian species such as fungi, yeast, invertebrates, insects and plants, functions to provide energy sources and protects the integrity of cells against various environmental stresses.[17] Several studies have reported that Tre acts as an antioxidant, which has been proved to be effective against lipid peroxidation.[18,19,20,21,22,23] Tre is a novel mTOR-independent autophagy enhancer It can activate autophagic flux and prevent the formation of cytoplasmic protein aggregation in cultured cells.[24] Tre has been demonstrated to protect against apoptosis in an autophagy-dependent manner.[25,26] Despite data that confirmed these properties of Tre, few studies have investigated the protective effect of Tre on Cd-induced nephrotoxicity till now. These results would provide a protective means against environmental Cd-induced renal damage and generate more comprehensive and reliable data for toxicological risk evaluation
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