EET-Based Therapeutics Mitigate Sorafenib-Associated Glomerular Cell Damage
Abhishek Mishra1, Marcus de Bourg2, Rawand S Mohamed2
1Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA.
Biomolecules
|September 27, 2025
Summary
This study shows that 8,9-epoxyeicosatrienoic acid (8,9-EET) analogs protect kidney cells from sorafenib toxicity. One analog, MDB-52a, reduced cell death and counteracted gene changes linked to kidney damage.
Area of Science:
- Nephrology
- Molecular Biology
- Pharmacology
Background:
- Sorafenib, a tyrosine kinase inhibitor, can cause kidney damage.
- Glomerular cells are key targets of sorafenib-induced nephrotoxicity.
- 8,9-epoxyeicosatrienoic acid (8,9-EET) analogs are investigated for protective effects.
Purpose of the Study:
- To investigate sorafenib-induced toxicity in human renal mesangial cells (HRMCs) and podocytes.
- To examine the protective potential of 8,9-EET analogs against sorafenib-induced kidney damage.
- To identify specific 8,9-EET analogs that mitigate sorafenib nephrotoxicity.
Main Methods:
- HRMCs and podocytes were exposed to sorafenib alone or with 8,9-EET analogs.
- Cell viability assays and caspase 3/7 activity measurements were performed.
- RNA sequencing and analysis of public kidney gene expression data (Nephroseq) were utilized.
Main Results:
- Sorafenib decreased cell viability and increased apoptosis in a dose-dependent manner.
- Five of twenty 8,9-EET analogs demonstrated significant cytoprotective effects.
- Sorafenib altered genes in cell cycle and Raf/MEK/ERK pathways; MDB-52a modulated ANGPTL4 and ACTA2 expression, correlating with glomerulosclerosis markers.
Conclusions:
- The 8,9-EET analog MDB-52a shows promise in counteracting sorafenib-induced gene disruptions.
- MDB-52a exhibits protective effects against sorafenib-related kidney damage in vitro.
- Targeting glomerular cells with 8,9-EET analogs may offer a therapeutic strategy for sorafenib nephrotoxicity.
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