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Updated: May 7, 2026
Assessment of Kidney Function in Mouse Models of Glomerular Disease
Published on: June 30, 2018
Expression patterns of RelA and c-mip are associated with different glomerular diseases following anti-VEGF therapy
Hassan Izzedine1, Melanie Mangier2, Virginie Ory2
1Department of Nephrology, Pitie-Salpetriere Hospital, Paris, France.
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.
Insights
Vascular endothelial growth factor (VEGF) targeted therapies can cause kidney damage. This study identifies two distinct mechanisms, involving RelA and c-mip proteins, underlying renal toxicity in patients receiving these anticancer treatments.
Area of Science:
- Nephrology
- Oncology
- Molecular Biology
Background:
- Renal toxicity is a significant side effect of vascular endothelial growth factor (VEGF) targeted anticancer therapies.
- Understanding the mechanisms of this toxicity is crucial for patient management.
Purpose of the Study:
- To investigate the distinct pathological mechanisms of renal damage induced by VEGF-targeted therapies.
- To identify molecular markers differentiating types of kidney injury in patients undergoing these treatments.
Main Methods:
- Analysis of 29 patients experiencing renal side effects from VEGF-targeted therapies.
- Histopathological examination and molecular analysis (VEGF, RelA, c-mip, complement factors, ADAMTS13) of renal biopsies.
- Correlation of molecular findings with clinical presentation and treatment type (RTKIs vs. anti-VEGF).
Main Results:
- Two distinct renal pathologies were observed: minimal change nephropathy/focal segmental glomerulopathy (MCN/FSG)-like lesions and thrombotic microangiopathy (TMA).
- MCN/FSG-like lesions were associated with decreased glomerular VEGF and increased c-mip, while TMA was linked to undetectable VEGF and high RelA abundance.
- RelA was found to inhibit c-mip transcription, a process reversed by RTKIs like sorafenib.
Conclusions:
- VEGF-targeted therapies induce distinct renal damage patterns characterized by MCN/FSG-like lesions or TMA.
- The proteins c-mip and RelA play opposing roles and define these two distinct types of VEGF inhibitor-induced nephrotoxicity.
- These findings may aid in predicting and managing renal side effects of anti-cancer therapies.
