Abstract: SA-PO267
Mapping Progression of Diabetic Kidney Disease (DKD) in Renin Adeno-Associated Virus (AAV) UNx db/db Mice Utilizing Time-Series RNA Sequencing
Session Information
- Diabetic Kidney Disease: Basic - 2
October 26, 2024 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Diabetic Kidney Disease
- 701 Diabetic Kidney Disease: Basic
Authors
- Marstrand-Jørgensen, Adam Bøgh, Gubra A/S, Hørsholm, Denmark
- Madsen, Martin Roenn, Gubra A/S, Hørsholm, Denmark
- Kaasboell, Ole Joergen, Tribune Therapeutics AS, Oslo, Norway
- Østergaard, Mette Viberg, Novo Nordisk A/S, Bagsvaerd, Hovedstaden, Denmark
- Dalbøge, Louise, Gubra A/S, Hørsholm, Denmark
- Christensen, Michael, Gubra A/S, 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/m mice (BKS.Cg-Dock7m +/+ Leprdb/J) served as healthy controls. One week after AAV injection, ReninAAV mice underwent UNx and subsequently randomized and stratified into 4 groups according to fed blood glucose levels and body weight measured 3 weeks post-UNx. ReninAAV UNx mice were terminated at 4, 8, 12 and 16 weeks (w4-w12) after UNx. Healthy db/m 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 glomerulosclerosis from w8 and albuminuria from w4. 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. Shifting gene 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 glomerulosclerosis and albuminuria 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.
Funding
- Commercial Support – Gubra A/S | Tribune Therapeutics AS