Identification of VEGF Signaling Inhibition-Induced Glomerular Injury in Rats through Site-Specific Urinary Biomarkers
Abstract
:1. Introduction
2. Results
2.1. Pharmacological Profile of ABT-123
2.2. Toxicity Profile of ABT-123 in Rats
2.3. Glomerular Ultrastructural Changes in Rats Treated with ABT-123
2.4. Urinary Biomarker Changes in Rats Treated with ABT-123
2.5. Gene Expression Changes in Rats Treated with ABT-123
3. Discussion
4. Materials and Methods
4.1. In Vitro and In Vivo Pharmacology
4.2. Animals, Treatment, and Sample Collection
4.3. Clinical Pathology and Histopathology Assessment
4.4. Electron Microscopic Assessment of the Kidney
4.5. Urinary Biomarker Analysis
4.6. Laser Capture Microdissection and Microarray Analysis
4.7. Statistical Analysis
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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VEGFRs | Non-Related Tyrosine Kinases | Serine/Threonine Kinases | |||
---|---|---|---|---|---|
Kinase | IC50 (nM) | Kinase | IC50 (nM) | Kinase | IC50 (nM) |
VEGFR-1 | 70 | SRC | >50,000 | AKT | >50,000 |
VEGFR-2 | 24 | IGFR | >50,000 | SGK | 11,000 |
VEGFR-3 | 54 | INSR | >50,000 | CDC2 | >50,000 |
LCK | 13,000 | PKA | >50,000 | ||
EGFR | >50,000 | ||||
HCK | >50,000 | ||||
cMET | >50,000 | ||||
LYN | >20,000 | ||||
FYN | >50,000 | ||||
FGR | >50,000 |
Sequence Code | Sequence Name | Sequence Description | Fold Change in Glomerulus | Fold Change in Kidney | ||
---|---|---|---|---|---|---|
Rat #1 | Rat #2 | Rat #1 | Rat #2 | |||
1367555_at | Alb | Albumin | −8.15 | −4.78 | −2.20 | −2.90 |
1367595_s_at | B2m | Beta-2 microglobulin | 1.11 | 1.13 | −1.06 | −1.23 |
1387965_at | Kim1 | Kidney injury molecule 1 | 1.10 | 2.19 | 6.55 | 2.19 |
1387011_at | Ngal | Neutrophil gelatinase-associated lipocalin | 1.73 | −1.20 | 2.96 | 4.08 |
1367581_a_at | Opn | Osteopontin | 1.82 | 2.30 | 2.79 | 2.90 |
1367784_a_at | Clu | Clusterin | 1.30 | 1.67 | 2.80 | 1.48 |
1388246_at | Clu | Clusterin | 1.47 | 1.96 | 1.50 | 1.05 |
1387218_at | Tff3 | Trefoil factor 3 | −14.96 | −9.34 | −1.11 | −1.21 |
1367774_at | GSTa3 | Glutathione S-transferase A3 | 1.26 | −1.77 | −1.17 | 1.03 |
1372297_at | GSTa4 | Glutathione S-transferase alpha 4 | −1.50 | −4.49 | −1.29 | −1.09 |
1386985_at | GSTm1 | Glutathione S-transferase mu 1 | 3.11 | 2.39 | 2.16 | 3.88 |
Sequence Code | Sequence Name | Sequence Description | Fold Change in Glomerulus | Fold Change in Kidney | ||
---|---|---|---|---|---|---|
Rat #1 | Rat #2 | Rat #1 | Rat #2 | |||
1373807_at | Vegfa | Vascular endothelial growth factor A | −1.03 | 1.22 | −1.00 | 1.14 |
1370081_a_at | Vegfa | Vascular endothelial growth factor A | −1.17 | 1.18 | −1.07 | 1.02 |
1380854_at | Vegfb | Vascular endothelial growth factor B | −1.08 | −6.07 | −1.01 | −1.31 |
1368463_at | Vegfc | Vascular endothelial growth factor C | −2.46 | −2.76 | −1.48 | −1.25 |
1387709_at | Vegfd | Vascular endothelial growth factor D | 1.17 | 1.44 | −1.13 | −1.15 |
1368919_at | Pgf | Placental growth factor | 1.66 | 2.28 | −1.17 | 1.20 |
1368918_at | Pgf | Placental growth factor | 1.48 | 1.89 | 1.31 | −1.29 |
1369087_at | Vegfr-1 | Vegf receptor 1 | −2.94 | −3.29 | −1.60 | −1.13 |
1367948_a_at | Vegfr-2 | Vegf receptor 2 | −2.51 | −2.21 | −3.30 | −2.45 |
1369216_a_at | Vegfr-3 | Vegf receptor 3 | 2.10 | 1.15 | 1.10 | −1.16 |
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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
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 StyleYang, 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 StyleYang, 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