Lead intoxication‐induced exosomes promote autophagy and apoptosis in renal proximal tubule cells by activating the adenosine 5'‐monophosphate‐activated protein kinase signaling

Abstract

AbstractLead (Pb) intoxication is known to damage the proximal tubules of kidney. Autophagy and apoptosis have been shown to be involved in a variety of renal injuries, but the underlying mechanisms remain largely unknown. In this study, we constructed a mice model of Pb intoxication and validated it against lead concentrations in blood and urine. Electron microscopy revealed that Pb promoted the accumulation of autophagosomes. Subsequent immunofluorescence and western blotting revealed that Pb intoxication suppressed the autophagic flux. Next, exosomes were isolated and extracted through ultracentrifugation, and were further identified by diameter analysis and marker detection. We also demonstrated that autophagy and apoptosis were enhanced in renal cells with exosomes of Pb expose. Furthermore, the specific mechanisms were explored by RNA sequencing and it was found that several targeted genes regulated by differential exosomal miRNAs and lncRNAs. Target genes accumulated in several signaling pathways, especially the adenosine 5'‐monophosphate‐activated protein kinase (AMPK) signaling. We found that Pb intoxication‐induced exosomes activated the AMPK signaling in renal proximal tubule cells. Furthermore, autophagy and apoptosis assays showed that GSK‐690693, an AMPK inhibitor, significantly alleviated exosome‐induced renal injuries by Pb intoxication. In conclusion, Pb‐mediated exosome‐induced autophagy and apoptosis via activating the AMPK signaling contributing to Pb‐induced nephrotoxicity in renal cells.