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Updated: Oct 10, 2025
Assessment of Kidney Function in Mouse Models of Glomerular Disease
Published on: June 30, 2018
Identification of VEGF Signaling Inhibition-Induced Glomerular Injury in Rats through Site-Specific Urinary
Yi Yang1, Kenneth Kowalkowski1, Rita Ciurlionis1
1Global Pharmaceutical Research and Development, AbbVie, 1 North Waukegan Road, North Chicago, IL 60064, USA.
Abstract:
Cancer therapies targeting the vascular endothelial growth factor (VEGF) signaling pathway can lead to renal damage by disrupting the glomerular ultrafiltration apparatus. The objective of the current study was to identify sensitive biomarkers for VEGF inhibition-induced glomerular changes in rats. Male Sprague-Dawley rats were administered an experimental VEGF receptor (VEGFR) inhibitor, ABT-123, for seven days to investigate the correlation of several biomarkers with microscopic and ultrastructural changes. Glomeruli obtained by laser capture microdissection were also subjected to gene expression analysis to investigate the underlying molecular events of VEGFR inhibition in glomerulus. ABT-123 induced characteristic glomerular ultrastructural changes in rats, including fusion of podocyte foot processes, the presence of subendothelial electron-dense deposits, and swelling and loss of fenestrations in glomerular endothelium. The subtle morphological changes cannot be detected with light microscopy or by changes in standard clinical chemistry and urinalysis. However, urinary albumin increased 44-fold as early as Day three. Urinary β2-microglobulin levels were also increased. Other urinary biomarkers that are typically associated with tubular injury were not significantly impacted. Such patterns in urinary biomarkers can provide valuable diagnostic insight to VEGF inhibition therapy-induced glomeruli injuries.
Insights
Vascular Endothelial Growth Factor (VEGF) inhibitors can cause kidney damage. Urinary albumin and β2-microglobulin are sensitive biomarkers for detecting VEGF inhibition-induced glomerular injury in rats.
Area of Science:
- Nephrology
- Oncology
- Pharmacology
Background:
- Cancer therapies targeting the vascular endothelial growth factor (VEGF) signaling pathway are crucial for tumor growth inhibition.
- VEGF pathway inhibition can paradoxically lead to renal damage by affecting the glomerular ultrafiltration apparatus.
Purpose of the Study:
- To identify sensitive urinary biomarkers for detecting early glomerular changes induced by VEGF receptor (VEGFR) inhibition.
- To correlate biomarker changes with microscopic and ultrastructural renal alterations in a rat model.
Main Methods:
- Male Sprague-Dawley rats were treated with an experimental VEGFR inhibitor (ABT-123) for seven days.
- Glomeruli were isolated using laser capture microdissection for gene expression analysis.
- Urinary biomarkers, including albumin and β2-microglobulin, were measured and correlated with ultrastructural glomerular changes.
Main Results:
- ABT-123 induced characteristic ultrastructural glomerular changes, including podocyte foot process fusion and endothelial fenestration loss.
- These subtle changes were not detectable by light microscopy or standard clinical chemistry.
- Urinary albumin showed a 44-fold increase by Day 3, and urinary β2-microglobulin levels also rose significantly.
Conclusions:
- Urinary albumin and β2-microglobulin are sensitive early biomarkers of VEGF inhibition-induced glomerular injury.
- Standard urinalysis and clinical chemistry assays are insufficient for detecting these specific renal changes.
- Monitoring these urinary biomarkers can provide valuable diagnostic insight for patients undergoing VEGF-targeted cancer therapies.
