Table 2.
Renal manifestations from pharmacologic VEGF inhibition in murine models
| Animal Model (Model/Transgene, Strain, Age) | Drug | Mechanism | Target | Dose, Route and Frequency | Effects | Reference |
|---|---|---|---|---|---|---|
| Wild-type mice, CD1, age not specified | Anti-VEGF antibody and mouse sFlt-1/Fc fusion protein (soluble VEGFR1) | Both treatments act to reduce circulating VEGF | VEGFA | 3.25 and 32.5 pM, IV, single dose | Both treatments induced proteinuria by 3 h after administration, which resolved after 24 h. Both treatments resulted in GEnC hypertrophy and detachment from the basement membrane, starting at 3 h post-treatment and persisting to 24 h | 17 |
| Wild-type mice, strain not specified, neonatal | Antibody to recombinant human VEGF165 | Reduction of circulating VEGFA | VEGFA | 100 µl/dose, IP, single dose on days 0, 2, 4, and 5 after birth | Decreased glomerular number and formation of abnormal glomeruli with poor cellularity and increased ECM. No significant changes in any nonglomerular vessels | 21 |
| Wistar Kyoto rats treated with antiglomerular basement membrane Ab, 12 wk | Mouse sFlt-1 plasmid | Soluble decoy receptor for VEGFR1. Reduction of circulating VEGFA | Soluble VEGFR1 | 500 μg, IM, 3 d before and 2 wk after injection of antiglomerular basement membrane Ab | Accelerated renal failure, proteinuria, interstitial fibrosis, endothelial cell loss. and downregulation of Nephrin in a model of rat crescentic GN | 35 |
| Wild-type mice, C57BL/6, 9–13 wk old | Axitinib (AG-013736) | Small molecule multitargeted TKI against VEGFR1–3, c-KIT, and PDGFR | VEGFR2, VEGFR1, VEGFR3, c-KIT, PDGFR | 25 mg/kg, IP, twice daily for 7, 14 or 21 d | Reduction in peritubular capillary density by 30% and glomerular capillary by 10% after 21 d of treatment. Dose dependent increase in proteinuria. Reduced glomerular capillary fenestrations. No increase in serum creatinine | 51 |
| For dose-response studies: 1, 10, or 100 mg/kg, oral gavage, twice daily for 7 d | ||||||
| Wild-type mice, C57BL/6, 9–13 wk old | Ad-sVEGFR1 | Adenoviral vector that expresses the extracellular domain of murine VEGFR1. Acts as soluble decoy receptor for VEGF | Soluble VEGFR1 | 1×109 plaque-forming units, tail vein, once | No significant reduction in peritubular capillary or glomerular capillary density. Reduced glomerular capillary fenestrations and increase proteinuria after 14 d | 51 |
| BALB/c(Bicc1/Bicc1) BPK model (murine phenocopy of ARPKD) and BALB/c wild-type controls, age not specified | Tesevatinib | TKI including EGFR, HER2/ErbB2, c-Src, and VEGFR2 | VEGFR2, HER2, EGFR2, ERBB2 | 7.5 and 15 mg/kg, IP, daily postnatal day 4–21 | Dose-dependent reduction in whole kidney size, total kidney weight; altered renal and liver morphology | 48 |
| PCK rat model (orthologous model of human ARPKD) and Sprague–Dawley wild type as control, age not specified | Tesevatinib | TKI including EGFR, HER2/ErbB2, c-Src, and VEGFR2 | VEGFR2, HER2, EGFR2, ERBB2 | 7.5 and 15 mg/kg, oral gavage, daily for 60 d (from postnatal day 30–90) | Dose-dependent reduction in whole kidney size, total kidney weight; altered renal and liver morphology | 48 |
| UUO model and folic acid nephropathy models in male wild-type C57BL/6 mice, 6–8 wk | Nintedanib (BIBF11220) | A multitargeted TKI that blocks PDGFR, VEGFR, FGFR, and Src family kinases | PDGFR, VEGFR, FGFR, SRC | 50 mg/kg, oral gavage, administered starting on day of UUO and then daily for 7 d | Attenuated renal fibrosis, inhibited activation of renal interstitial fibroblasts, and suppressed expression of proinflammatory cytokines after UUO | 49 |
| db/db and db/m male C57BL/6 mice, 6 wk | dRK6 (a D-amino acid derivative of RK6) | An arginine-rich anti-VEGF hexapeptide that binds with VEGF-A, and blocks the interaction between VEGFA (mainly VEGF165 and VEGF121) and the VEGFRs | VEGFA | 50 μg, SC, three times per week starting at 8 wk of age and lasting until 12 wk (short-term) and 20 wk (long-term) | Both short-term and long-term treatment had decreased creatinine clearance compared with control db/db mice. Long-term treatment also exacerbated albuminuria, mesangial matrix expansion, and glomerulomegaly as compared with vehicle-treated db/db and short-term dRK6-treated db/db mice | 36 |
| Perinatal wild-type mice (exact age not specified) | DC101 | mAb against the extracellular portion of the VEGFR2 | VEGFR2 | 0.08 mg/dose, IP, on postnatal days 2 and 4 | Large renal cysts, impaired glomerulogenesis (hypocellular), and increased albuminuria by 3 wk of age | 50 |
| Male Wistar Kyoto rats 280–300 g, age not specified | Sunitinib | A multitargeted TKI including PDGFRα and PDGFRβ, VEGFR1, VEGFR2, and VEGFR3, and FMS-like tyrosine kinase-3 | VEGFR1, VEGFR2, VEGFR3, PDGFRα, PDGFRβ, FMS-like tyrosine kinase-3 | Low dose (7 mg/kg), intermediate (14 mg/kg) or high (26.7 mg/kg), oral gavage, once daily for 8 d | All doses associated with hypertension and proteinuria. Intermediate and high doses were associated with endothelial swelling. High-dose only was associated with fibrin deposits in glomerular capillaries and small arteries | 52 |
IV, intravenous; GEnC, glomerular endothelial cells; IP, intraperitoneal; ECM, extracellular matrix; Ab, antibody; IM, intramuscular; c-KIT, tyrosine-protein kinase Kit; PDGFR, PDGFR receptor; ARPKD, autosomal-recessive polycystic kidney disease; PCK, polycystic kidney; UUO, unilateral ureteric obstruction; EGFR, EGF receptor; FGFR, fibroblast growth factor receptor; SC, subcutaneous.