Acute kidney injury(AKI)is a heterogeneous clinical complication with no existing definite or particular therapies.Therefore,molecular mechanisms and approaches for treating acute kidney injury are in urgent need.Here...Acute kidney injury(AKI)is a heterogeneous clinical complication with no existing definite or particular therapies.Therefore,molecular mechanisms and approaches for treating acute kidney injury are in urgent need.Herein,we demonstrated that dexrazoxane(DXZ),a U.S.Food and Drug Administration(FDA)-approved cardioprotective drug,can both functionally and histologically attenuate cisplatin or ischemia-reperfusion injury-induced AKI in vitro and in vivo via inhibiting ferroptosis specifically.This effect is characterized by decreasing lipid peroxidation,shown by the biomarker of oxidative stress 4-hydroxynonenal(HNE)and prostaglandinendoperoxide synthase 2(Ptgs2),while reversing the downregulation of glutathione peroxidase 4(GPX4)and ferritin 1(FTH-1).Mechanistically,the results revealed that DXZ targeted at the renal tubule significantly inhibits ferroptosis by suppressingα-amino-β-carboxymuconate-ε-semialdehyde decarboxylase(ACMSD).Furthermore,the conjugation of dexrazoxane and polysialic acid(DXZ-PSA)is specifically designed and utilized to enhance the therapeutic effect of DXZ by long-term effect in the kidney,especially retention and targeting in the renal tubules.This study provides a novel therapeutic approach and mechanistic insight for AKI by inhibiting ferroptosis through a new type drug DXZPSA with the enhanced renal distribution.展开更多
基金This work was supported by grants from Zhejiang Provincial Natural Science Foundation of China(No.LZ22H050001)the National Natural Science Foundation of China(Nos.81970573,81670651,81900683,82000637,and 82173662)+1 种基金Zhejiang provincial program for the Cultivation of High-level Innovative Health talents,Natural Science Foundation of Shanghai(No.20ZR1410400)Medical Health Science and Technology Project of Zhejiang Provincial Health Commission(No.2020KY538).
文摘Acute kidney injury(AKI)is a heterogeneous clinical complication with no existing definite or particular therapies.Therefore,molecular mechanisms and approaches for treating acute kidney injury are in urgent need.Herein,we demonstrated that dexrazoxane(DXZ),a U.S.Food and Drug Administration(FDA)-approved cardioprotective drug,can both functionally and histologically attenuate cisplatin or ischemia-reperfusion injury-induced AKI in vitro and in vivo via inhibiting ferroptosis specifically.This effect is characterized by decreasing lipid peroxidation,shown by the biomarker of oxidative stress 4-hydroxynonenal(HNE)and prostaglandinendoperoxide synthase 2(Ptgs2),while reversing the downregulation of glutathione peroxidase 4(GPX4)and ferritin 1(FTH-1).Mechanistically,the results revealed that DXZ targeted at the renal tubule significantly inhibits ferroptosis by suppressingα-amino-β-carboxymuconate-ε-semialdehyde decarboxylase(ACMSD).Furthermore,the conjugation of dexrazoxane and polysialic acid(DXZ-PSA)is specifically designed and utilized to enhance the therapeutic effect of DXZ by long-term effect in the kidney,especially retention and targeting in the renal tubules.This study provides a novel therapeutic approach and mechanistic insight for AKI by inhibiting ferroptosis through a new type drug DXZPSA with the enhanced renal distribution.
