Prednisone is a synthetic glucocorticoid that is commonly used in both human and veterinary medication.Now,it is also recognized as an emerging environmental contaminant.Pregnantwomenmay be exposed to prednisone activ...Prednisone is a synthetic glucocorticoid that is commonly used in both human and veterinary medication.Now,it is also recognized as an emerging environmental contaminant.Pregnantwomenmay be exposed to prednisone actively or passively throughmultiple pathways and cause developmental toxicity to the fetus.However,the impact of prenatal prednisone exposure(PPE)on fetal kidney development remains unclear.In this study,pregnant mice were administered prednisone intragastrically during full-term pregnancy with different doses(0.25,0.5,or 1 mg/(kg·day)),or at the dose of 1 mg/(kg·day)in different gestational days(GD)(GD0-9,GD10-18,or GD0-18).The pregnant mice were euthanized on GD18.HE staining revealed fetal kidney dysplasia,with an enlarged glomerular Bowman’s capsule space and a reduced capillary network in the PPE groups.The expression of the podocyte and the mesangial cell marker genes was significantly reduced in the PPE groups.However,overall gene expression in renal tubules and collecting ducts were markedly increased.All of the above effects were more pronounced in high-dose,full-term pregnancy,and female fetuses.Studies on the mechanism of the female fetal kidney have revealed that PPE reduced the expression of Six2,increased the expression of Hnf1β,Hnf4α,and Wnt9b,and inhibited the expression of glial cell line-derived neurotrophic factor(GDNF)and Notch signaling pathways.In conclusion,this study demonstrated that there is a sex difference in the developmental toxicity of PPE to the fetal kidney,and the time effect is manifested as full-term pregnancy>early pregnancy>mid-late pregnancy.展开更多
Despite a continuing increase in the number of patients suffering from chronic kidney disease,currently available treatments for these patients,such as dialysis and kidney transplantation,are imperfect.The kidney is a...Despite a continuing increase in the number of patients suffering from chronic kidney disease,currently available treatments for these patients,such as dialysis and kidney transplantation,are imperfect.The kidney is also a critical target organ vulnerable to the toxicity of various new drugs,and the lack of a reliable in vitro culture model imposes a severe limitation on drug discovery.Although the development of induced pluripotent stem cells(iPSCs)revolutionized strategies in biomedical fields,the complexity of the kidney imposed additional challenge to the application of this technology in kidney regeneration.Nonetheless,the recent advancement in our understanding on the developmental origin of kidney progenitor cells and the mechanisms of their reciprocal induction and self-organization has boosted research in kidney regeneration.Research since then has demonstrated that kidney organoids derived from iPSCs can serve as a useful model for drug discovery and toxicity screening,as well as for disease modeling,especially in combination with gene editing techniques.Moreover,attempts at kidney organoid implantation in animals have suggested their potential as an alternative source of kidney transplantation.In this review,we summarize recent progress on the generation of kidney organoids,as well as the obstacles that remain.展开更多
Background:Determining the expression and functions of aquaporins(AQPs)in the adult kidney has generated important information about the roles of this protein family in the renal regulation of water homeostasis.Howeve...Background:Determining the expression and functions of aquaporins(AQPs)in the adult kidney has generated important information about the roles of this protein family in the renal regulation of water homeostasis.However,limited information describes the expression of AQPs in fetal kidneys,and most reports on fetal renal AQPs originate from animal studies.Although there are the maturation and regulation of the renalconcentrating mechanism,the ways in which changes in the expression of AQPs contribute to the formation of urine during the perinatal period remain unclear.Data sources:This review summarizes current knowledge about the spatial and temporal expression patterns of AQP1,AQP2,AQP3,and AQP4 in the fetal and postnatal kidneys in different animal species and in human beings.Results:AQP1 and AQP2 expression can be detected earlier in gestation in human beings and sheep compared with mice and rats.AQP1 expression is detected earlier in the proximal tubules than the expression of AQP2,AQP3,and AQP4 in the collecting ducts.Conclusion:Further studies investigating the regulation of AQPs during kidney development may provide insights into normal water-handling mechanisms and the pathophysiology of fetal kidneys,which may determine new directions for the clinical treatment of kidney diseases.展开更多
基金supported by the National Key Research and Development Program of China(No.2020YFA0803900)the National Natural Science Foundation of China(No.81872943)。
文摘Prednisone is a synthetic glucocorticoid that is commonly used in both human and veterinary medication.Now,it is also recognized as an emerging environmental contaminant.Pregnantwomenmay be exposed to prednisone actively or passively throughmultiple pathways and cause developmental toxicity to the fetus.However,the impact of prenatal prednisone exposure(PPE)on fetal kidney development remains unclear.In this study,pregnant mice were administered prednisone intragastrically during full-term pregnancy with different doses(0.25,0.5,or 1 mg/(kg·day)),or at the dose of 1 mg/(kg·day)in different gestational days(GD)(GD0-9,GD10-18,or GD0-18).The pregnant mice were euthanized on GD18.HE staining revealed fetal kidney dysplasia,with an enlarged glomerular Bowman’s capsule space and a reduced capillary network in the PPE groups.The expression of the podocyte and the mesangial cell marker genes was significantly reduced in the PPE groups.However,overall gene expression in renal tubules and collecting ducts were markedly increased.All of the above effects were more pronounced in high-dose,full-term pregnancy,and female fetuses.Studies on the mechanism of the female fetal kidney have revealed that PPE reduced the expression of Six2,increased the expression of Hnf1β,Hnf4α,and Wnt9b,and inhibited the expression of glial cell line-derived neurotrophic factor(GDNF)and Notch signaling pathways.In conclusion,this study demonstrated that there is a sex difference in the developmental toxicity of PPE to the fetal kidney,and the time effect is manifested as full-term pregnancy>early pregnancy>mid-late pregnancy.
文摘Despite a continuing increase in the number of patients suffering from chronic kidney disease,currently available treatments for these patients,such as dialysis and kidney transplantation,are imperfect.The kidney is also a critical target organ vulnerable to the toxicity of various new drugs,and the lack of a reliable in vitro culture model imposes a severe limitation on drug discovery.Although the development of induced pluripotent stem cells(iPSCs)revolutionized strategies in biomedical fields,the complexity of the kidney imposed additional challenge to the application of this technology in kidney regeneration.Nonetheless,the recent advancement in our understanding on the developmental origin of kidney progenitor cells and the mechanisms of their reciprocal induction and self-organization has boosted research in kidney regeneration.Research since then has demonstrated that kidney organoids derived from iPSCs can serve as a useful model for drug discovery and toxicity screening,as well as for disease modeling,especially in combination with gene editing techniques.Moreover,attempts at kidney organoid implantation in animals have suggested their potential as an alternative source of kidney transplantation.In this review,we summarize recent progress on the generation of kidney organoids,as well as the obstacles that remain.
基金supported by the Karen Elise Jensens Foundation,Lundbeck Foundation,AP Møller Foundation,and the National Natural Science Foundation of China(No.81370869).
文摘Background:Determining the expression and functions of aquaporins(AQPs)in the adult kidney has generated important information about the roles of this protein family in the renal regulation of water homeostasis.However,limited information describes the expression of AQPs in fetal kidneys,and most reports on fetal renal AQPs originate from animal studies.Although there are the maturation and regulation of the renalconcentrating mechanism,the ways in which changes in the expression of AQPs contribute to the formation of urine during the perinatal period remain unclear.Data sources:This review summarizes current knowledge about the spatial and temporal expression patterns of AQP1,AQP2,AQP3,and AQP4 in the fetal and postnatal kidneys in different animal species and in human beings.Results:AQP1 and AQP2 expression can be detected earlier in gestation in human beings and sheep compared with mice and rats.AQP1 expression is detected earlier in the proximal tubules than the expression of AQP2,AQP3,and AQP4 in the collecting ducts.Conclusion:Further studies investigating the regulation of AQPs during kidney development may provide insights into normal water-handling mechanisms and the pathophysiology of fetal kidneys,which may determine new directions for the clinical treatment of kidney diseases.
