Abstract: FR-PO283
Colony-Stimulating Factor 1 Receptor Inhibitor (PLX3397) Attenuates Kidney Injury and Fibrosis Caused by Repeated Low-Dose Cisplatin
Session Information
- Onconephrology: From AKI to CKD and Everything in Between
November 03, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Onconephrology
- 1700 Onconephrology
Authors
- Hayase, Naoki, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, United States
- Sung, Cathy, National Institute on Deafness and Other Communication Disorders, Bethesda, Maryland, United States
- Hu, Xuzhen, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, United States
- Yuen, Peter S.T., National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, United States
- Cunningham, Lisa, National Institute on Deafness and Other Communication Disorders, Bethesda, Maryland, United States
- Star, Robert A., National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, United States
Background
Cisplatin is a standard drug to treat many solid organ cancers. However, cisplatin can cause significant side effects including irreversible hearing loss and short-term (AKI) and long-term (fibrosis) renal impairment. Fernandez et al found that a mouse model of repeated low dose cisplatin (RLDC) treatment exhibited significant hearing loss and loss of cochlear mechanosensory hair cells. The colony-stimulating factor 1 receptor inhibitor PLX3397 ablated cochlear macrophages (>95% of immune cells in cochlea) and prevented hearing loss and hair cell loss. A recent report suggested that depletion of resident macrophages may mitigate renal fibrosis in the RLDC model. Therefore, we hypothesized that PLX3397 also would protect against cisplatin-induced nephrotoxicity.
Methods
CBAJ/CX3CR1GFP/+ (het) mice were used to label macrophages with GFP. Mice underwent three cycles of cisplatin treatment (3 mg/kg/day I.P. cisplatin for 4 days followed by a 10-day recovery). We fed mice with vehicle- or PLX3397-formulated chow one week prior, and then via daily oral gavage during the cisplatin cycles. We harvested kidneys, blood, and inner ears at 20 days after the last cisplatin injection for histological and biochemical analyses. Tissue platinum (cisplatin) was measured by inductively coupled plasma mass spectrometry.
Results
Mice that received cisplatin had increased plasma BUN and NGAL levels. In addition, cisplatin-treated mice had significant tubular injury and fibrosis, while administering PLX3397 significantly improved all parameters. We found that cisplatin increased CX3CR1+ cells in the kidney (without vs. with cisplatin, 8.6 ± 1.3 vs. 20.2 ± 2.6 cells/high-power field (HPF), n = 4-5/group, p = 0.001). We confirmed that PLX3397 treatment ablated CX3CR1+ cells in the kidney (Cisplatin without vs. with PLX3397, 20.2 ± 2.6 vs.1.5 ± 0.6 cells/HPF, n = 4-5/group, p < 0.001). Moreover, PLX3397 markedly prevented the accumulation of platinum in the kidney.
Conclusion
PLX3397 treatment mitigated cisplatin-induced kidney injury and renal fibrosis via ablation of renal CX3CR1+ cells. Additionally, PLX3397 treatment also decreased accumulation of cisplatin in the kidney. The pathogenetic roles of CX3CR1+ cells in cisplatin-induced nephrotoxicity of the RLDC model need to be elucidated in future studies.
Funding
- NIDDK Support