Abstract
Renal toxicity constitutes a dose-limiting side effect of anticancer therapies targeting vascular endothelial growth factor (VEGF). In order to study this further, we followed up 29 patients receiving this treatment, who experienced proteinuria, hypertension, and/or renal insufficiency. Eight developed minimal change nephropathy/focal segmental glomerulopathy (MCN/FSG)-like lesions and 13 developed thrombotic microangiopathy (TMA). Patients receiving receptor tyrosine kinase inhibitors (RTKIs) mainly developed MCN/FSG-like lesions, whereas TMA complicated anti-VEGF therapy. There were no mutations in factor H, factor I, or membrane cofactor protein of the complement alternative pathway, while plasma ADAMTS13 activity persisted and anti-ADAMTS13 antibodies were undetectable in patients with TMA. Glomerular VEGF expression was undetectable in TMA and decreased in MCN/FSG. Glomeruli from patients with TMA displayed a high abundance of RelA in endothelial cells and in the podocyte nuclei, but c-mip was not detected. Conversely, MCN/FSG-like lesions exhibited a high abundance of c-mip, whereas RelA was scarcely detected. RelA binds in vivo to the c-mip promoter and prevents its transcriptional activation, whereas RelA knockdown releases c-mip activation. The RTKI sorafenib inhibited RelA activity, which then promoted c-mip expression. Thus, our results suggest that c-mip and RelA define two distinct types of renal damage associated with VEGF-targeted therapies.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing
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Adult
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Aged
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Angiogenesis Inhibitors / adverse effects*
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Animals
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Base Sequence
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Binding Sites
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Biomarkers / metabolism
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Carrier Proteins / genetics
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Carrier Proteins / metabolism*
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Case-Control Studies
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Cell Line
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Female
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Gene Expression Regulation
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Glomerulosclerosis, Focal Segmental / chemically induced
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Glomerulosclerosis, Focal Segmental / diagnosis
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Glomerulosclerosis, Focal Segmental / enzymology
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Humans
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Hypertension / chemically induced
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Hypertension / diagnosis
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Hypertension / enzymology
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Kidney Diseases / chemically induced*
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Kidney Diseases / diagnosis
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Kidney Diseases / enzymology
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Kidney Glomerulus / drug effects*
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Kidney Glomerulus / enzymology
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Kidney Glomerulus / pathology
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Male
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Mice
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Mice, Knockout
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Middle Aged
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Molecular Sequence Data
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Nephrosis, Lipoid / chemically induced
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Nephrosis, Lipoid / diagnosis
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Nephrosis, Lipoid / enzymology
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Niacinamide / adverse effects
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Niacinamide / analogs & derivatives*
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Phenylurea Compounds / adverse effects*
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Predictive Value of Tests
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Promoter Regions, Genetic
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Protein Kinase Inhibitors / adverse effects*
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Proteinuria / chemically induced
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Proteinuria / diagnosis
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Proteinuria / enzymology
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Renal Insufficiency / chemically induced
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Renal Insufficiency / diagnosis
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Renal Insufficiency / enzymology
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Sorafenib
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Thrombotic Microangiopathies / chemically induced
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Thrombotic Microangiopathies / diagnosis
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Thrombotic Microangiopathies / enzymology
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Transcription Factor RelA / deficiency
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Transcription Factor RelA / genetics
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Transcription Factor RelA / metabolism*
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Transcription, Genetic
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Transfection
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Vascular Endothelial Growth Factors / antagonists & inhibitors*
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Vascular Endothelial Growth Factors / metabolism
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Young Adult
Substances
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Adaptor Proteins, Signal Transducing
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Angiogenesis Inhibitors
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Biomarkers
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CMIP protein, human
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Carrier Proteins
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Phenylurea Compounds
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Protein Kinase Inhibitors
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RELA protein, human
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Rela protein, mouse
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Transcription Factor RelA
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Vascular Endothelial Growth Factors
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Niacinamide
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Sorafenib