DOI: 10.1002/ame2.70094
Temporal glomerular gene expression dynamics during disease progression in a mouse model of hypertension-accelerated diabetic kidney disease
Adam B.Marstrand-Jørgensen1
Frederikke Emilie Sembach1
Maria Ougaard1
Ditte Hansen2
Mette Viberg Østergaard3
Henrik H.Hansen1
Louise S.Dalbøge1
Ole Jørgen Kaasbøll4
Michael Christensen1
1.Gubra A/S,Hørsholm,Denmark2.Department of Nephrology,Herlev-Gentofte Hospital,University of Copenhagen,Herlev,Denmark;Department of Clinical Medicine,University of Copenhagen,Copenhagen,Denmark3.Cardiovascular & Renal Disease Therapeutic area,Novo Nordisk A/S,Måløv,Denmark4.Tribune Therapeutics AS,Oslo,Norway
摘要：Background:The current understanding of diabetic kidney disease(DKD)has sig-nificant gaps regarding the underlying pathogenesis.In this study,we aimed to char-acterize the temporal progression of DKD using a state-of-the-art mouse model of hypertension-accelerated disease,integrating kidney biomarker analysis,histopathol-ogy,and glomerular transcriptomic profiling.
Methods:Female diabetic db/db mice received a single intravenous dose of adeno-associated virus-mediated renin overexpression(ReninAAV,week 5)and underwent uninephrectomy(UNx,week 4).db/db UNx-ReninAAV mice were terminated at weeks 1,4,8,and 12(n=7-8 per group).Female db/m mice were used as healthy controls.Study endpoints included plasma and urine biochemistry,glomerulosclerosis scoring,quantitative kidney histology,and RNA sequencing of glomeruli isolated using laser-capture microdissection.
Results:db/db UNx-ReninAAV mice developed progressive albuminuria(from week 4)and glomerulosclerosis(from week 8).A pathway analysis of clustered gene regula-tions revealed broad glomerular transcriptome perturbations with signatures of in-creased extracellular matrix(ECM)turnover from week 8 and early onset of metabolic dysfunction.Markers of glomerular cell types and injury exhibited temporal regula-tion over the course of DKD,with early and sustained downregulation of endothelial markers,heterogeneous regulation of podocyte markers,and significant mesangial and parietal epithelial aberrations.Furthermore,the upregulation of cell injury mark-ers confirmed progressive glomerular injury in the model.
Conclusion:The db/db UNx-ReninAAV mouse model exhibits distinct temporal dy-namics in glomerular cell markers,metabolic dysregulation,ECM remodeling,and in-jury.Together,these results highlight the utility of the db/db UNx-ReninAAV model as a relevant preclinical platform for studying progressive DKD.
机标关键词：hypertensionexpressiondynamicskidneymousemodelgeneaccelerated
论文发表日期：2025-12-30
在线出版日期：2026-03-25（本平台首次上网日期，不代表文献的发表时间）
页数：13( 2115-2127 )
英文信息