Abstract: FR-PO988
Shared and Distinct Renal Transcriptome Signatures in Three Standard Mouse Models of CKD
Session Information
- CKD Mechanisms: From Mendel to Mars
November 03, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 2303 CKD (Non-Dialysis): Mechanisms
Authors
- Marstrand-Jørgensen, Adam Bøgh, Gubra, Hørsholm, Denmark
- Sembach, Frederikke Emilie, Gubra, Hørsholm, Denmark
- Bak, Stine Thorhauge, Gubra, Hørsholm, Denmark
- Ougaard, Maria Katarina, Gubra, Hørsholm, Denmark
- Christensen-Dalsgaard, Mikkel, Gubra, Hørsholm, Denmark
- Jensen, Ditte Marie, Gubra, Hørsholm, Denmark
- Secher, Thomas, Gubra, Hørsholm, Denmark
- Heimbürger, Sebastian Møller Nguyen, Gubra, Hørsholm, Denmark
- Fink, Lisbeth N., Gubra, Hørsholm, Denmark
- Hansen, Ditte, Kobenhavns Universitet Det Natur- og Biovidenskabelige Fakultet, Frederiksberg, Denmark
- Hansen, Henrik H., Gubra, Hørsholm, Denmark
- Østergaard, Mette Viberg, Gubra, Hørsholm, Denmark
- Christensen, Michael, Gubra, Hørsholm, Denmark
- Dalbøge, Louise, Gubra, Hørsholm, Denmark
Background
Various mouse models with differing disease etiologies are available in preclinical chronic kidney disease (CKD) research. Characterizing these models according to their renal transcriptomics enables better selection of the optimal model for preclinical drug discovery studies. We therefore characterized the kidney transcriptome signature of three well-established models of CKD, i.e. unilateral ureter obstruction (UUO), unilateral ischemic reperfusion injury (uIRI) and adenine-supplemented diet feeding (ADI).
Methods
Male C57BL/6J mice were used in all studies. Mice underwent UUO or uIRI surgery and were terminated two- and six-weeks post-surgery, respectively. Sham-operated mice served as controls. For ADI, mice received an adenine-supplemented diet or control diet for six weeks. Endpoints included plasma biochemistry, kidney histology and RNA sequencing.
Results
All three models displayed increased macrophage infiltration (F4/80) and fibrosis (Col1a1). An excessive number of renal differentially expressed genes (≥11,000) was observed in all three models, with a notable overlap in their transcriptome signatures. Gene expression markers of inflammation, fibrogenesis and kidney injury supported histological findings in the models. A subset of genes showed model-specific changes, including genes representing current drug targets for CKD (e.g., Ednrb, Nr3c2, Glp1r, Flt1 and Ptch1), emphasizing the applicability of the three CKD models in preclinical target and drug discovery.
Conclusion
While the UUO, uIRI and ADI mouse models of CKD demonstrate notable commonalities in renal transcriptome signatures, model-specific transcriptional changes in genes encoding current drug targets emphasize that the three models have different utility in preclinical drug discovery.
Funding
- Commercial Support – Gubra A/S