Abstract: FR-PO1067
The Adenine-Induced Mouse Model of CKD Shows Rapid Development of Impaired Kidney Function, Renal Fibrosis, Muscle Wasting, and Anemia
Session Information
- CKD Mechanisms: Progression, Fibrosis, and Beyond
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
- Ougaard, Maria Katarina, Gubra, Hoersholm, Denmark
- Sembach, Frederikke Emilie, Gubra, Hoersholm, Denmark
- Nøhr-Meldgaard, Jacob, Gubra, Hoersholm, Denmark
- Marstrand-Jørgensen, Adam Bøgh, Gubra, Hoersholm, Denmark
- Hansen, Henrik H., Gubra, Hoersholm, Denmark
- Christensen, Michael, Gubra, Hoersholm, Denmark
Background
Translational rodent models are essential to identify more efficacious treatment options for patients with chronic kidney disease (CKD). However, most preclinical CKD models do not demonstrate impaired kidney function as determined by decreased glomerular filtration rate (GFR). Here, we characterize an adenine diet-induced (ADI) mouse model of CKD that enables clinical translational studies of CKD.
Methods
Male C57BL/6j mice (11 weeks old) were randomized into study groups (n=8-10 per group) based on body weight. ADI mice received a control diet from study day -2 and a CKD-inducing diet containing 0.2% adenine from study day 1, while control mice received a control diet from day -2 and continued with it throughout the study period. All groups received oral vehicle dosing once daily starting from day 1 until termination. Transdermal GFR (tGFR), urine creatinine-to-albumin ratio, and plasma cystatin C(pCyC) were evaluated at week 3 and 5. Blood was collected for glycated haemoglobin analysis, and gastrocnemius muscle and kidney tissue were sampled and weighed. Kidneys were collected for RNA sequencing or processed for histological evaluation of markers of macrophage infiltration (F4/80) and fibrosis (Col1a1).
Results
Compared to controls, ADI mice showed a significant tGFR decline correlating with an increased pCyC and marked albuminuria at 3 and 5 weeks after diet-induction. At termination, ADI mice showed significantly decreased glycated haemoglobin (14.7 vs 17.6 g/dL) and gastrocnemius muscle weight compared to mice receiving the control diet (0.12 vs 0.15 g). Furthermore, Quantitative kidney histomorphometric analysis demonstrated an increase in kidney fibrosis (Col1a1) and macrophage infiltration (F4/80) in ADI mice. Consistent with tGFR decline and kidney histology, the renal transcriptome signature in ADI mice indicated upregulation of gene expression markers of fibrosis (e.g. Col1a1, Grem1), inflammation (e.g. Il6, Il1b), and angiogenesis (e.g. Ednra, Agt).
Conclusion
ADI mice rapidly develop functional, biochemical and histological hallmarks of CKD complicated by anaemia and muscle wasting. Consequently, ADI mice are highly relevant in preclinical target and drug discovery for CKD.
Funding
- Commercial Support – Gubra