Abstract: SA-PO106
Glomerular Injury and Progressive Cardiac Dysfunction in the Obese ZSF1 Rat, a New Model of Diabetic Nephropathy and Heart Failure with Preserved Ejection Fraction
Session Information
- Diabetic Kidney Disease: Basic - III
October 27, 2018 | Location: Exhibit Hall, San Diego Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Diabetic Kidney Disease
- 601 Diabetic Kidney Disease: Basic
Authors
- Di marco, Elyse, AstraZeneca, MOLNDAl, Sweden
- Michaëlsson, Erik, AstraZeneca, MOLNDAl, Sweden
- Ericson, Charlotte, AstraZeneca, MOLNDAl, Sweden
- Behrendt, Margareta, CVRM IMED Biotech, Gothenburg, Sweden
- Stromstedt, Maria, AstraZeneca, MOLNDAl, Sweden
- Soderberg, Magnus, AstraZeneca, MOLNDAl, Sweden
- Wikstrom, Johannes, AstraZeneca, MOLNDAl, Sweden
- Granqvist, Anna, AstraZeneca, MOLNDAl, Sweden
Background
Efforts to develop effective therapies against interlinked cardiac and renal diseases are hampered by the lack of preclinical models. We have investigated whether the hypertensive, diabetic, obese ZSF1 rat represents a valid experimental disease model for diabetic nephropathy (DN) and heart failure with preserved ejection fraction (HFpEF).
Methods
The renal (glomerular filtration rate- GFR, albuminuria, histology) and the cardiac (functional non-invasive imaging/invasive haemodynamics, histology) phenotypes were investigated in obese and lean male ZSF1 rats. Uninephrectomy (UNX) was performed in obese rats at 12-weeks of age followed by administration of high-salt diet (HSD) and treatment with ACE inhibitor Lisinopril for 10 weeks.
Results
Obese UNX ZSF1 rats displayed progressive albuminuria, reduced GFR and glomerular injury evidenced by increased desmin and reduced WT1 immunostaining, reduced podocyte-specific gene expression (podocin, nephrin, WT1) compared to lean ZSF1 rats. The renal histological phenotype was severely aggravated by HSD, consistent with marked increases in urinary biomarkers KIM-1, NGAL and Cystatin C. UNX rats fed HSD showed an increase in NTproBNP, a marker of cardiac stress, in line with progressive cardiac hypertrophy and impaired ventricular relaxation. Lisinopril treatment of UNX+HSD-rats had no effect on the renal phenotype or cardiac relaxation, but markedly improved systolic function.
Conclusion
The obese ZSF1 rat with UNX is a suitable model of renal dysfunction with progressive glomerular injury and the addition of HSD elicits a HFpEF phenotype. This model now allows us to investigate potential therapies targeting these interlinked diseases.
Funding
- Commercial Support – AstraZeneca