Abstract: SA-PO0324
Charting Diabetic Kidney Disease Progression via Time Course RNA Sequencing in ReninAAV UNx db/db Mice
Session Information
- Diabetic Kidney Disease: Basic and Translational Science Advances - 2
November 08, 2025 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Diabetic Kidney Disease
- 701 Diabetic Kidney Disease: Basic
Authors
- Ougaard, Maria Katarina, Gubra, Hørsholm, Denmark
- Marstrand-Jørgensen, Adam, Gubra, Hørsholm, Denmark
- Christensen, Michael, Gubra, Hørsholm, Denmark
- Østergaard, Mette Viberg, Gubra, Hørsholm, Denmark
- Kaasboell, Ole Joergen, Tribune, Oslo, Norway
- Dalbøge, Louise, Gubra, Hørsholm, Denmark
Background
The adeno-associated virus-mediated renin overexpression (ReninAAV) uninephrectomized (UNx) db/db mouse model of diabetic kidney disease (DKD) recapitulates hallmarks of DKD complicated by hypertension. Gaps persist in our understanding regarding temporal patterns of glomerular gene expression and pathophysiology during hypertensive DKD. The present longitudinal study characterized glomerular transcriptome changes during disease progression in ReninAAV UNx db/db mice.
Methods
Female db/db (BKS.Cg-Dock7m +/+ Leprdb/J) received a single i.v. dose of renin-encoding AAV. Untreated db/+ mice (BKS.Cg-Dock7m +/+ Leprdb/J) served as healthy controls. One week after AAV injection, ReninAAV mice underwent UNx. The mice were randomized and stratified into 4 groups according to fed blood glucose levels and body weight measured 3 weeks post-UNx. The study was initiated 4 weeks after UNx and the ReninAAV UNx mice were terminated at 1, 4, 8, and 12 weeks. Healthy db/+ mice were terminated at 12 weeks. Endpoints included urine and plasma biochemistry, kidney histology (Col1a1 and glomerulosclerosis scoring) and RNA sequencing of glomeruli isolated by laser-capture microdissection.
Results
ReninAAV UNx db/db mice showed onset of progressive albuminuria from w4 and glomerulosclerosis from w8. More than 3,000 differentially expressed genes (DEGs) were detected in glomeruli at each timepoint, including fibrosis, inflammation and glomerular injury markers. A subset of DEGs were also clinical drug targets. Temporal regulation was noted across all categories, including late downregulation of Ednrb and Glp1r and late upregulation of Col1a1 and Col3a1. Additionally, temporal changes were seen in interacting targets, e.g. a shift from early temporary upregulation of Adam17 to late upregulation of Adam10.
Conclusion
The ReninAAV UNx db/db mouse model of hypertensive DKD demonstrates progressive albuminuria and glomerulosclerosis paralleled by dynamic shifts in glomerular gene expression signatures. Notably, the identification of temporal patterns of gene expression provides novel insights into DKD pathophysiology and progression. This underscores the ReninAAV UNx db/db mouse as an applicable model of human DKD in preclinical target and drug discovery.