Therapeutic Inhibition of VEGF Signaling and Associated Nephrotoxicities

Abstract

Inhibition of vascular endothelial growth factor A (VEGFA)/vascular endothelial growth factor receptor 2 (VEGFR2) signaling is a common therapeutic strategy in oncology, with new drugs continuously in development. In this review, we consider the experimental and clinical evidence behind the diverse nephrotoxicities associated with the inhibition of this pathway. We also review the renal effects of VEGF inhibition's mediation of key downstream signaling pathways, specifically MAPK/ERK1/2, endothelial nitric oxide synthase, and mammalian target of rapamycin (mTOR). Direct VEGFA inhibition via antibody binding or VEGF trap (a soluble decoy receptor) is associated with renal-specific thrombotic microangiopathy (TMA). Reports also indicate that tyrosine kinase inhibition of the VEGF receptors is preferentially associated with glomerulopathies such as minimal change disease and FSGS. Inhibition of the downstream pathway RAF/MAPK/ERK has largely been associated with tubulointerstitial injury. Inhibition of mTOR is most commonly associated with albuminuria and podocyte injury, but has also been linked to renal-specific TMA. In all, we review the experimentally validated mechanisms by which VEGFA-VEGFR2 inhibitors contribute to nephrotoxicity, as well as the wide range of clinical manifestations that have been reported with their use. We also highlight potential avenues for future research to elucidate mechanisms for minimizing nephrotoxicity while maintaining therapeutic efficacy.

Keywords: VEGF; hypertension; nitric oxide; proteinuria; signaling.

Figure 1.

VEGFA-VEGFR2 signaling pathways and their pharmacological inhibition occur across the glomerular filtration barrier. VEGFA is released from podocytes and binds to its receptor (VEGFR2) on glomerular endothelial cells. (i) Bevacizumab and ranibizumab are mAbs against VEGFA and inhibit angiogenesis through IgG antibody interaction with all of its isoforms. (ii) Aflibercept is a recombinant fusion protein comprising binding domains for VEGFR1 and VEGFR2 attached to the Fc portion of human IgG1, and acts as a soluble decoy receptor or “VEGF trap.” (iii) Ramucirumab is a fully humanized IgG1 mAb that specifically inhibits VEGFR2 by targeting its extracellular domain. (iv) TKIs such as sunitinib, pazopanib, sorafenib, and axitinib target VEGFR2, as well as interfere with the activity of additional RTKs such as PDGF receptor, fibroblast growth factor receptor, and EGF receptor, which all share a similar structure. (v) Agents such as vemurafenib and dabrafenib have been recently developed to specifically target B-Raf, a component of the intracellular MAPK/ERK intracellular pathway. (vi) mTOR inhibitors such as temsirolimus, ridaforolimus, and everolimus are used across several malignancies and act downstream of the phosphatidylinositide 3-kinase (PI3K)/AKT signal transduction pathway. Ab, antibody; BRAF, B-Raf Proto-Oncogene; EF, endothelial fenestrations; FP, foot process; GBM, glomerular basement membrane; GEnC, glomerular endothelial cell; P, Podocyte.

Figure 2.

Inhibition of VEGFA-VEGFR2 signaling has differential downstream effects, depending on the therapeutic target. (A) During treatment with anti-VEGF ligand, podocyte secreted VEGFA is sequestered and does not bind to either podocyte or endothelial VEGFR2 (large X). This leads to increased NF-κB signaling and RelA translocation to the nucleus in both glomerular endothelial cells as well as podocytes. CFH is downregulated on glomerular endothelial cells, which leads to increased complement activation. (B) Treatment with TKIs allows VEGFA to bind to glomerular endothelial and podocyte VEGFR2, but inhibits downstream signaling (small x's). This induces RelA retention in the cytoplasm and c-mip overexpression in the podocyte, leading to alterations in the cytoskeleton and nephrotic syndrome. The effects of TKIs on complement activation remain unclear.