Identification of VEGF Signaling Inhibition-Induced Glomerular Injury in Rats through Site-Specific Urinary Biomarkers
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....
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-11-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/22/23/12629 |
| _version_ | 1797507763298893824 |
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| author | Yi Yang Kenneth Kowalkowski Rita Ciurlionis Wayne R. Buck Keith B. Glaser Daniel H. Albert Eric A. G. Blomme |
| author_facet | Yi Yang Kenneth Kowalkowski Rita Ciurlionis Wayne R. Buck Keith B. Glaser Daniel H. Albert Eric A. G. Blomme |
| author_sort | Yi Yang |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-10T04:53:04Z |
| format | Article |
| id | doaj.art-303ab7d571f24aa7899afe4e5febdaf2 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T04:53:04Z |
| publishDate | 2021-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-303ab7d571f24aa7899afe4e5febdaf22023-11-23T02:25:29ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-11-0122231262910.3390/ijms222312629Identification of VEGF Signaling Inhibition-Induced Glomerular Injury in Rats through Site-Specific Urinary BiomarkersYi Yang0Kenneth Kowalkowski1Rita Ciurlionis2Wayne R. Buck3Keith B. Glaser4Daniel H. Albert5Eric A. G. Blomme6Global Pharmaceutical Research and Development, AbbVie, 1 North Waukegan Road, North Chicago, IL 60064, USAGlobal Pharmaceutical Research and Development, AbbVie, 1 North Waukegan Road, North Chicago, IL 60064, USAGlobal Pharmaceutical Research and Development, AbbVie, 1 North Waukegan Road, North Chicago, IL 60064, USAGlobal Pharmaceutical Research and Development, AbbVie, 1 North Waukegan Road, North Chicago, IL 60064, USAGlobal Pharmaceutical Research and Development, AbbVie, 1 North Waukegan Road, North Chicago, IL 60064, USAGlobal Pharmaceutical Research and Development, AbbVie, 1 North Waukegan Road, North Chicago, IL 60064, USAGlobal Pharmaceutical Research and Development, AbbVie, 1 North Waukegan Road, North Chicago, IL 60064, USACancer 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.https://www.mdpi.com/1422-0067/22/23/12629vascular endothelial growth factorglomerular injuryurinary biomarkers |
| spellingShingle | Yi Yang Kenneth Kowalkowski Rita Ciurlionis Wayne R. Buck Keith B. Glaser Daniel H. Albert Eric A. G. Blomme Identification of VEGF Signaling Inhibition-Induced Glomerular Injury in Rats through Site-Specific Urinary Biomarkers International Journal of Molecular Sciences vascular endothelial growth factor glomerular injury urinary biomarkers |
| title | Identification of VEGF Signaling Inhibition-Induced Glomerular Injury in Rats through Site-Specific Urinary Biomarkers |
| title_full | Identification of VEGF Signaling Inhibition-Induced Glomerular Injury in Rats through Site-Specific Urinary Biomarkers |
| title_fullStr | Identification of VEGF Signaling Inhibition-Induced Glomerular Injury in Rats through Site-Specific Urinary Biomarkers |
| title_full_unstemmed | Identification of VEGF Signaling Inhibition-Induced Glomerular Injury in Rats through Site-Specific Urinary Biomarkers |
| title_short | Identification of VEGF Signaling Inhibition-Induced Glomerular Injury in Rats through Site-Specific Urinary Biomarkers |
| title_sort | identification of vegf signaling inhibition induced glomerular injury in rats through site specific urinary biomarkers |
| topic | vascular endothelial growth factor glomerular injury urinary biomarkers |
| url | https://www.mdpi.com/1422-0067/22/23/12629 |
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