The Mechanism Of Cadmium Nephrological Toxicity And Medication—Disregulation Of Calcium Homeostasis And Autophagy Mediated The Kidney Injury Caused By Cadmium

Environmental exposure and occupational exposure to cadmium?Cd?has a serious threat to human health.In recent years,some studies has analyzed the methods of preventing and controlling Cd pollution and explored the mechanism of Cd detoxification.However,Cd caused a series of complex effects after absorbed by the human body.So far,the mechanism of Cd-caused various diseases is still unclear,and the methods for Cd detoxification are still in study.We previously had conducted on the study of Cd-disrupted calcium ion(Ca²⁺)homeostasis in mouse renal tubular epithelial cells?mRTEC?,which inhibited autophagy and induced apoptosis,as well as the intervention of Ca²⁺sensing receptor?CaSR?agonist R-467.However,the roles of R467 in animal models,as well as the mechanism of Cd-disrupted Ca²⁺homeostasis in renal tubular epithelial cells are still unclear.In this study,these questions are aim to be explored,and which may provide basis for the Cd detoxification and prevention of kidney injury.In this study,the renal functional parameters in urine and blood were detected in mice exposed to Cd for 28 days.The results showed that Cd exposure increased urine protein content,induced kidney injury molecule-1?KIM-1?expression and malondialdehyde?MDA?level,as well as kidney apoptosis in mice,which suggest that long-term Cd exposure causes kidney injury.To further explore the mechanism of Cd-induced kidney injury,we examined autophagic flux in kidneys of Cd-exposed mice.The results showed that Cd exposure induced the autophagy markers LC3B-II and P62protein,which indicated that autophagic flux was inhibited after Cd exposed.To verify the relationship between autophagy and apoptosis,the autophagy inhibitor chloroquine?CQ?was applied.After injection of CQ for 14 days,increased apoptosis and upregulated kidney injury molecule-1 expression were investigated,as well as increased the urine protein content and MDA level.It suggests long-term inhibition of autophagy would cause kidney injury.In addition,our results also showed that CaSR agonist R467 could restore Cd-inhibited autophagic flux,reduce Cd-induced kidney apoptosis and injury.To analyze and verify the relationship between Cd-induced renal toxicity and Ca²⁺homeostasis,Ca²⁺levels and its related proteins of the endoplasmic reticulum?ER?in mouse renal tubular epithelial cells were studied.The Ca²⁺levels in cytoplasm and endoplasmic reticulum were detected after treating cells with different concentrations of Cd,and the results showed that Cd caused increase of the Ca²⁺levels in cytoplasm but decrease in ER.To further investigate the underlying mechanism,the expression of sarcoplasmic reticulum/endoplasmic reticulum Ca²⁺-ATPase?SERCA?was detected,which maintains the concentration of Ca²⁺in the endoplasmic reticulum calcium store.The results showed that Cd treatment down-regulated the expression of SERCA,but not through the mRNA level.By detection the effect of Cd on the stability of SERCA protein and the degradation pathway,the results showed that Cd treatment accelerated the degradation rate of SERCA by the proteasome,which reduces the stability of SERCA and down-regulates the level of SERCA protein.Treatment with SERCA inhibitor thapsigargin?TG?proved that inhibition of SERCA could induce inhibition of autophagy and apoptosis.In summary,Cd exposure accelerated SERCA degradation in mRTEC cells,down-regulated SERCA protein levels,and prevented cytoplasmic Ca²⁺reabsorb back to the ER.The rising cytoplasmic Ca²⁺inhibit the autophagic flux and induce apoptosis.In animal models,the regulation of autophagy and Ca²⁺homeostasis prevents Cd-induced kidney apoptosis and injury.