| Ochratoxin A(OTA)is a risk factor for food safety and has been detected in the blood samples from the population.It has been reported that OTA induced a variety of toxicological effects on animal body and human body including neurotoxicity,nephrotoxicity and hepatotoxicity.The kidney is considered to be the target organs of OTA.However,the role of nutrients in reducing the toxicity of OTA and its mechanism remain to be further studied.Besides,kidney is an organ rich in mitochondria and closely related to the energy metabolism Therefore,in this study,renal cells and kidney tissues were used to study the protective mechanism of nutrient on OTA-induced energy metabolism disorders and kidney injury.(1)Using proteomics technology,we found that OTA inhibits the energy metabolism of kidney and liver,and activates the process of apoptosis and ubiquitination.In addition,the expression of Grp75 protein is closely regulated by OTA.By using the OTA-induced acute nephrotoxicity model,human renal tubular epithelial cells and Grp75 gene silencing cell line,we confirmed the role of OTA on Grp75 expression.Inhibition of Grp75 can stimulate the up-regulation of Kim-1 and the down-regulation of Lonp-1 under OTA treatment,suggesting that Grp75 protein could medicate a novel channel for renal injury.(2)Zinc is an essential trace element in the human body.It is widely involved in the regulation of antioxidant system and the stability of DNA.In this study,we explored the relationship between zinc ions and cell apoptosis and the regulation of cell energy metabolism.We found that zinc ions alleviates the apoptosis induced by OTA,and Grp75 was regulated by zinc against OTA-induced toxicity.Besides,ZNF447 protein is involved in the zinc-medicated cytoprotection,and pointed out that PARP and?-H2AX were further activated in the ZNF447 knockout cell line under OTA treatment.We also confirmed that zinc can enhance the cellular energy supply to improve cell motility,and restore the impaired energy metabolism caused by OTA.Moreover,under the condition of OTA induced cytotoxicity,zinc can promote the release of exosomes,and activates the intracellular regulatory factors for the exosome secretion.Animal experiments also showed that zinc supplementation could relieve OTA-induced nephrotoxicity.Zinc is also considered to have synergistic effects with troxerutin to better alleviate OTA-induced renal tubular epithelial cell damage in vitro.This result showed that the protective mechanism of zinc and troxerutin may be different ia alleviating OTA-induced cell damage.(3)Troxerutin is a natural flavonoid that is considered to reduce the inflammatory response of cells.The effect of troxerutin on OTA-induced nephrotoxicity was studied for the first time.The results showed that troxerutin alleviated the OTA-induced disorder of glucose and lipid inetabolism,reduced the activity of brown adipose,and improved renal function,inflammation,renal lipid accumulation and cell injury.In order to further explain the effect of troxerutin on kidney diseases,the renal fibrosis model was used,and found that troxerutin can improve energy metabolism,inflammatory reaction,collagen deposition,lipid synthesis,and eventually relieve the process of renal fibrosis.We also explored the relationship between the activation of brown adipose and the regulation of renal injury by establishing a model of brown adipose transplantation in mice.It was confirmed that brown adipose transplantation could relieve kidney fibrosis in mice.In conclusion,based on exploring the toxic mechanism of OTA,this study confirmed that zinc and troxerutin can alleviate the energy metabolism disorder and OTA-induced toxicity.Furthermore,the relationship between systemic energy metabolism disorder and renal disease is also discussed.This study provides a theoretical basis for the effects of nutrients on toxic damage and cytoprotection,provides new sights for the prevention and control of diseases. |
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