The use of inhibitors of vascular endothelial growth factor (VEGF)/vascular endothelial growth factor receptor 2 (VEGFR2) signaling for the treatment of cancer has increased over the last decade. This signaling pathway plays a fundamental role in angiogenesis and also in kidney physiology. The emergence of anti-angiogenic therapies has led to adverse nephrotoxic effects, despite improving the outcomes of patients. In this review, we will present the different anti-angiogenic therapies targeting the VEGFR pathway in association with the incidence of renal manifestations during their use. In addition, we will discuss, in detail, the pathophysiological mechanisms of frequent renal diseases such as hypertension, proteinuria, renal dysfunction, and electrolyte disorders. Finally, we will outline the cellular damage described following these therapies.

BACKGROUND AND AIMS Tumor angiogenesis is one of the therapeutic targets used in oncology, to limit cancer growth and spreading. The main angiogenesis signalling pathway is mediated by the vascular endothelial growth factor (VEGF) that binds to its tyrosine kinase receptor (VEGFR), mainly expressed on endothelial cells. The antiangiogenic therapy could target the VEGF ligand (anti-VEGF), or its receptors by inhibition of kinase activity (tyrosine kinase inhibitor, TKI) such as sorafenib. The toxicity of antiangiogenic therapies is a growing concern in clinical use. Indeed, nephrotoxicity is a critical side-effect that leads to discontinuation of therapy. Renal histological illustration of this toxicity is minimal change nephropathy/focal segmental glomerulosclerosis (MCNS/FSGS) and thrombotic micro-angiopathy (TMA), involving two distinct cell types, podocytes and endothelial cells respectively. Podocytes are the main source of VEGF and express VEGFR in the glomerulus. Mechanisms linking TKI therapy to podocyte dysfunction and nephrotic level proteinuria are still poorly understood. The working hypothesis is that nephrotoxicity of sorafenib is primarily through its effect on glomerular podocytes. METHOD Based on LC-MS/MS proteomic analysis, we have identified dysregulated cellular pathways on sorafenib-exposed podocytes. We validated these results by western blotting and immunofluorescence staining, on a cultured podocyte line exposed to sorafenib (2.5 µmol/L, 24-h). RESULTS Our results showed that sorafenib inhibits the downstream signalling pathways of VEGFR on podocytes, which induce injury by decreasing the expression of podocyte-specific markers (WT1, podocin). This is associated with podocyte morphology changes with podocyte cytoskeleton damages (actin and microtubules) and focal adhesions loss. We identified a novel podocyte target of sorafenib: the GSK3β. Indeed, sorafenib reduces significantly GSK3β inhibitory phosphorylation. Moreover, GSK3β regulates Tau, microtubule-associated proteins (MAP) and key regulator of microtubules remodelling. We show that tau phosphorylation increases significantly in sorafenib-treated cells. Furthermore, we found that sorafenib impairs the autophagic flux in podocytes, as indicated by an increase in LC3-II/LC3-I ratio in western blot, reflect of autophagosomes accumulation in podocytes. These results indicate that GSK3β overactivity induced by sorafenib participates in the disruption of the microtubules through tau phosphorylation, which interferes with cellular vesicle trafficking and blocks autophagic flux in podocytes. In addition, sorafenib leads to podocyte apoptosis through induction of endoplasmic reticulum (ER) stress (GADD153 protein induction and its nuclear translocation) and mitochondrial dysfunction. ER stress induced a decrease in podocyte protein synthesis with increased eIF2α phosphorylation. Sorafenib also causes mitochondrial membrane potential loss and mitochondrial depolarization. CONCLUSION Thus, in the current study, we show that sorafenib has a direct effect on podocytes, modulating specific signalling pathways to induce podocyte damage and ultimately glomerular lesions. However, we have to confirm the clinical relevance of our results on kidney biopsies from patients diagnosed with nephrotic syndrome following sorafenib treatment.