Role Of Nrf2 Mediated Antioxidative Defense Response And UPR^mt In Cadmium Induced-renal Mitochondrial Damage Of Chicken

Cadmium（Cd）is a kind of heavy metal contaminants which is harmful to animal and human health,especially,the effect of poultry toxicity in ecological environment is more obvious.Kidney is a target organ for the toxicity of Cd,however,the mechanism of nephrotoxicity to poultry kidneys remains unclear.In this study,male Hyland white chickens were fed with diets which contained different concentrations of CdCl₂.Renal pathological alteration was observed and related indicators such as renal function,mitochondrial dysfunction,oxidative stress,mitochondrial unfolded protein response,the expression of nuclear receptor,CYP450s and Nrf2 signaling pathway related genes were detected.The results indicated that:（1）Cd exposure induced tubular epithelial cell swelling,granules,vacuolar degeneration,renal tubules arranged disorder and increased renal interstitial space,which shows that Cd has nephrotoxicity.Cd-induced mitochondrial swelling,sacral breaks,and vacuolization of renal cells indicating that mitochondria may be the target organelles for Cd nephrotoxicity.（2）Exposure of low-dose Cd（<35 mg）up-regulated the expression of mitochondrial unfolded protein-related factors（SIRT1,PGC-1α,TFAM,Nrf1,and HTRA2）,induced UPR^mt.High-dose（>70 mg）Cd exposure significantly down-regulated the expression of unfolded protein related factors and inhibited UPR^mt.It indicated that cadmium could damage mitochondria through interference with UPR^mt,which might be one of the mechanisms of cadmium-induced nephrotoxicity.（3）Cd exposure could increase the contents of H₂O₂ and MDA in kidney tissue,decrease the activity of antioxidant enzymes（T-SOD,CAT,POD,Cu-Zn SOD）and induce oxidative stress;Cd exposure could also upregulate the expression of Nrf2,and then increased the Nrf2 signaling regulates expression level of targeting factors（HO-1,NQO1,GST,CAT,SOD1,SOD2,SOD3,GCLC,GCLM）,but the renal T-AOC levels decreased significantly.It indicated that Cd exposure could activate the Nrf2 antioxidant defense response,But the oxidative stress was not relieved.（4）Cd exposure could induce the contents of CYP450 and Cyt b5,CYP450s（APND,ERND,AH and NCR）activities,expression levels of nuclear receptor（AHR/CAR/PXR）and transcription levels of CYPs subunit（CYP1A1、CYP1A5、CYP2C18、CYP2C45、CYP3A4、CYP3A9）,indicating that Cd exposure could activate nuclear xenobiotic receptors（AHR/CAR/PXR）responses,disrupt cytochrome P450 homeostasis and CYP450 isoforms transcription.In conclusion,Cd can cause nephrocyte and mitochondrial damage by inducing oxidative stress,activating antioxidant defense mechanism by activating Nrf2 signaling pathway,disrupting UPR^mtt and cytochrome P450 homeostasis,triggering nuclear receptor（AHR/CAR/PXR）response.