Abstract
Vascular endothelial growth factor A (VEGFA) and its receptor VEGFR2 are the main targets of antiangiogenic therapies, and proteinuria is one of the common adverse events associated with the inhibition of the VEGFA/VEGFR2 pathway. The proteinuric kidney damage induced by VEGFR2 tyrosine kinase inhibitors (TKIs) is characterized by podocyte foot process effacement. TKI therapy promotes the formation of abnormal endothelial‒podocyte crosstalk, which plays a key role in TKI-induced podocyte injury and proteinuric nephropathy. This review article summarizes the underlying mechanism by which the abnormal endothelial‒podocyte crosstalk mediates podocyte injury and discusses the possible molecules and signal pathways involved in abnormal endothelial‒podocyte crosstalk. What is more, we highlight the molecules involved in podocyte injury and determine the essential roles of Rac1 and Cdc42; this provides evidence for exploring the abnormal endothelial‒podocyte crosstalk in TKI-induced nephrotoxicity.
Highlights
Vascular endothelial growth factor A (VEGFA) and its receptor VEGFR2 are the main drivers of tumor angiogenesis and the main targets of antiangiogenic therapies [1]
ROS by suppressing the redox enzyme p66Shc [62]. This crosstalk between endothelial cells and podocytes can protect podocytes from injury, which has been confirmed by the improvement of diabetic nephropathy in mice through exogenous administration of activated protein C (aPC) [63]
Many studies have been conducted on the treatment of proteinuric nephropathies, and a variety of agents have been proven to be good at reducing proteinuria [12,13,115,116,117,135,136,137,138], but most of them target the renin-angiotensin-aldosterone system (RAAS) system and no drugs have been reported to be effective at improving the clinical outcome of proteinuric nephropathy induced by VEGFAVEGFR2 inhibitors
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. These drugs lead to some unignorable adverse events such as proteinuria, hypertension, hand-foot syndrome, etc. Among these adverse events, proteinuria attracts attention for its high incidence, great impact on cancer treatment, and lack of effective interventions. Proteinuria was the most frequent adverse event contributing to dose reduction; it resulted in 52%. The administration of ACEIs even compromised the anticancer efficacy of antiangiogenic drugs [17,18] These facts make proteinuria an urgent problem, and the key to solving this problem is to thoroughly understand the mechanism of proteinuria induced by VEGFA-VEGFR2 inhibitors
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