| Acute kidney injury(AKI)is a multidisciplinary clinical critical syndrome with high morbidity,unknown pathogenesis,difficulty in early diagnosis,lack of effective treatment,and poor prognosis.In recent years,both clinical and basic studies have confirmed that the occurrence of AKI is accompanied by an imbalance of iron metabolism in the kidneys,which has a significant impact on the progression and prognosis of AKI.Therefore,regulation of iron homeostasis in AKI may become a new strategy for the diagnosis and mitigation of AKI.We have done a lot of works on the intrinsic link between iron metabolism and AKI,and found that ferroportin(Slc40a1,FPN)expressed at the basolateral of renal tubular epithelial cells during the pathological process of AKI could re-transfered intracellular non-heme iron into blood circulation,thereby reducing AKI damage.In-depth syudies have found that non-heme iron deficiency significantly aggravated AKI.Inferred that the core factor aggravating the pathological process of AKI might only be produced by catalytic iron(heme or nonheme iron present in damaged cells that were not bound by proteins and have the activity of catalyzing the production of superoxide).In this regard,we propose the hypothesis that heme-catalyzed iron and non-heme-catalyzed iron aggravating renal tubular epithelial cells injury through mediated oxidative stress,thereby exacerbating AKI.This paper has carried out delicated research on this.Iron deficiency is the most common micronutrient deficiency worldwide.While iron deficiency is known to suppress embryonic organogenesis,its effect on the adult organ in the context of clinically relevant damage has not been considered.Therefore,in this papper we firstly investigated the effect of iron deficiency on the pathological process of nephrotoxic intrinsic AKI.We fed mice with iron deficient diet(Fe D)to induced iron deficiency mice status,and established a mouse model of nephrotoxic AKI(Cis-AKI)by intraperitoneal injection of cisplatin.Report that iron deficiency is a risk factor for AKI.Iron deficiency exacerbated cisplatin-induced AKI by markedly increasing non-heme catalytic iron and Nox4 protein which together catalyze production of hydroxyl radicals followed by protein and DNA oxidation,apoptosis and ferroptosis.In further studies we found that crosstalk between non-heme catalytic iron/Nox4 and downstream oxidative damage generated a mutual amplification cycle that facilitated rapid progression of cisplatin-induced AKI.In addition,rhabdomyolysis(Rh)-AKI(Rh-AKI)model established by intramuscular injection of glycerol in the mouse,we also found that iron deficiency also exacerbated AKI via increasing catalytic heme-iron.Heme-iron induced lipid peroxidation and DNA oxidation by interacting with Nox4-independent mechanisms,promoting p53/p21 activity and cellular senescence.Our data suggests that correcting iron deficiency and/or targeting specific catalytic iron species are strategies to mitigate AKI in a wide range of patients with diverse forms of kidney injury.Hence,the regulatory mechanisms of catalytic iron deteriorated AKI was further studied.In was cleared that catalytic iron has long been thought to underlie the pathogenesis of AKI,but its biochemistry is undefined.Here,we further delineated the contribution of heme and non-heme catalytic iron species to the onset and progression of rhabdomyolysis(Rh)-induced AKI and identify cellular mitigation strategies in the kidney.We use a nephron-specific knockout of the iron exporter ferroportin(FPN,Slc40a1),in which excessive non-heme iron and heme are confined to the proximal tubule,in combination with deletions of anti-lipid reactive oxygen species(ROS)protein Gpx4 and pro-oxidant protein Nox4 to identify the mechanism of injury.Within hours of Rh induction,heme-iron produced lipid ROS and lipid peroxidation which activated ferroptosis and initiated kidney injury.Subsequent upregulation of heme oxygenase enzymes generated non-heme catalytic iron and stimulated the production of hydroxyl radicals by concurrently upregulated Nox4.Crosstalk between non-heme catalytic iron/Nox4 and terminal steps of oxidative damage generated a mutual amplification cycle,driving the production of hydroxyl radicals and late stages of RhAKI.FPN and Gpx4 converged to suppress Rh-AKI minimizing heme catalytic iron and lipid ROS in early stages of Rh-AKI,respectively,while FPN protected the kidney in late stages of Rh-AKI by minimizing non-heme catalytic iron.In addition,lipid ROS during early stages facilitated late stages of Rh-AKI by fueling superoxide and peroxide species.Indeed,by removing heme and non-heme catalytic iron or by scavenging hydroxyl radicals we quantitatively rescued Rh-AKI.In sum,we demonstrate a feasible strategy for the efficacious therapeutic treatment of Rh-AKI by suppressing redoxmediated tissue injury.The studies in this paper clarifies the regulatory mechanism and molecular targets of different catalytic iron forms in promoting AKI,and helps to reveal the important role of catalytic iron in the pathological process of AKI.Thus,the molecular mechanism by which catalytic iron induces oxidative stress,damaging and aggravating AKI was clarified.Which would provide a comprehensive understanding of the scientific connotation of catalytic iron in injured AKI,and provide a more in-depth theoretical basis for the research and development of anti-AKI drugs. |
