Abstract: SA-PO094
Renoprotective Effect of IL-34 Inhibition on Cisplatin-Induced Nephrotoxicity in Mouse
Session Information
- AKI: Mechanisms - Primary Injury and Repair - II
November 09, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Acute Kidney Injury
- 103 AKI: Mechanisms
Authors
- Wada, Yukihiro, Showa University School of Medicine, Tokyo, Japan
- Iyoda, Masayuki, Showa University School of Medicine, Tokyo, Japan
- Matsumoto, Kei, Showa University School of Medicine, Tokyo, Japan
- Suzuki, Taihei, Showa University School of Medicine, Tokyo, Japan
- Tachibana, Shohei, Showa University School of Medicine, Tokyo, Japan
- Kanazawa, Nobuhiro, Showa University School of Medicine, Tokyo, Japan
- Shibata, Takanori, Showa University School of Medicine, Tokyo, Japan
Background
Interleukin (IL)-34 is reported to mediate macrophage (Mø) proliferation and to be associated with kidney disease progression. However, the physiological properties of IL-34 on tubular epithelial cell (TEC) injury remain unclear. Thus, we investigated the effect of IL-34 on TEC damage caused by cisplatin nephrotoxicity (CP-N).
Methods
7-week-old male C57BL/6 (B6) mice (n=16) were fasted for 8 hours and then induced CP-N by intraperitoneal injection (IP) of CP (25 mg/kg) on day 0. Groups of animals were given either anti mouse IL-34 antibody (CP+anti-IL-34 Ab, 400 ng/kg, n=8) or vehicle (CP+V, n=8) daily by IP from day -1 to day 2. Three age-matched male B6 mice were used as normal control (NC). All mice were sacrificed on day 3. In addition, mouse renal proximal TECs (MRTEpiC) were cultured to analyze the inhibitory effects of IL-34 on CP-induced TEC apoptosis. Cells were stimulated with CP (2 μg/mL), then treated with or without anti-IL-34 Ab (1000 pg/mL).
Results
Compared to the NC, CP+V mice exhibited marked acute kidney injury (AKI) and upregulated expression of IL-34 and its receptors, C-FMS and PTP-ζ. Compared to the vehicle treatment, anti-IL-34 Ab treatment significantly suppressed the protein levels of IL-34 and its receptors in CP-N mice; it also significantly improved serum Cr levels, ameliorated the numbers of casts/HPF, and suppressed the increased numbers of F4/80+, TUNEL+, and caspase-3+ cells in CP-N mice. The renal transcript levels of Kim-1, MIP-1/CCL3, TNF-α, and Bax were significantly lower in the CP+anti-IL-34 Ab mice than in the CP+V mice. Furthermore, CP+anti-IL-34 Ab mice showed significantly less renal infiltration of CD11b+F4/80+TNF-α+ cells. In vitro, stimulation with CP induced the expression of IL-34 and its receptors in MRTEpiC. Treatment with anti-IL-34 Ab significantly suppressed CP-induced caspase-3 and Bax expression with degradation of ERK1/2 phosphorylation in the damaged MRTEpiC.
Conclusion
These results indicated that IL-34 secreted from damaged TEC binds to its receptors and aggravates CP-N. Treatment with anti-IL-34 Ab directly prevented CP-induced TEC apoptosis by inhibiting the phosphorylation of ERK1/2, and the blocking of IL-34 might have indirectly attenuated CP-N via the suppression of cytotoxic Mø proliferation. Thus, IL-34 may be a therapeutic target for AKI.
Funding
- Government Support - Non-U.S.