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Volume 22
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10.3390/ijms222312629
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Article

Identification of VEGF Signaling Inhibition-Induced Glomerular Injury in Rats through Site-Specific Urinary Biomarkers

by
Yi Yang
*,
Kenneth Kowalkowski
,
Rita Ciurlionis
,
Wayne R. Buck
,
Keith B. Glaser
,
Daniel H. Albert
and
Eric A. G. Blomme
Global Pharmaceutical Research and Development, AbbVie, 1 North Waukegan Road, North Chicago, IL 60064, USA
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2021, 22(23), 12629; https://doi.org/10.3390/ijms222312629
Submission received: 24 September 2021 / Revised: 15 November 2021 / Accepted: 17 November 2021 / Published: 23 November 2021
(This article belongs to the Special Issue Nephrotoxicity 2020)
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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.
Keywords: vascular endothelial growth factor; glomerular injury; urinary biomarkers vascular endothelial growth factor; glomerular injury; urinary biomarkers

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MDPI and ACS Style

Yang, Y.; Kowalkowski, K.; Ciurlionis, R.; Buck, W.R.; Glaser, K.B.; Albert, D.H.; Blomme, E.A.G. Identification of VEGF Signaling Inhibition-Induced Glomerular Injury in Rats through Site-Specific Urinary Biomarkers. Int. J. Mol. Sci. 2021, 22, 12629. https://doi.org/10.3390/ijms222312629

AMA Style

Yang Y, Kowalkowski K, Ciurlionis R, Buck WR, Glaser KB, Albert DH, Blomme EAG. Identification of VEGF Signaling Inhibition-Induced Glomerular Injury in Rats through Site-Specific Urinary Biomarkers. International Journal of Molecular Sciences. 2021; 22(23):12629. https://doi.org/10.3390/ijms222312629

Chicago/Turabian Style

Yang, Yi, Kenneth Kowalkowski, Rita Ciurlionis, Wayne R. Buck, Keith B. Glaser, Daniel H. Albert, and Eric A. G. Blomme. 2021. "Identification of VEGF Signaling Inhibition-Induced Glomerular Injury in Rats through Site-Specific Urinary Biomarkers" International Journal of Molecular Sciences 22, no. 23: 12629. https://doi.org/10.3390/ijms222312629

APA Style

Yang, Y., Kowalkowski, K., Ciurlionis, R., Buck, W. R., Glaser, K. B., Albert, D. H., & Blomme, E. A. G. (2021). Identification of VEGF Signaling Inhibition-Induced Glomerular Injury in Rats through Site-Specific Urinary Biomarkers. International Journal of Molecular Sciences, 22(23), 12629. https://doi.org/10.3390/ijms222312629

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