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ABSTRACT: Introduction
Interleukin-34 (IL-34) shares a receptor (cFMS) with colony stimulating factor-1 (CSF-1), and these two ligands mediate macrophage proliferation. However, in contrast to CSF-1, the influence of IL-34 on tubular epithelial cells (TECs) injury remains unclear. We investigated the physiological effects of IL-34 on TEC damage caused by cisplatin nephrotoxicity (CP-N).Methods
Mice were administered anti-mouse IL-34 antibody (anti-IL-34 Ab; 400 ng/kg) or vehicle from 1 day before and up to 2 days after CP-N induction. In vitro, mouse renal proximal TECs (MRPTEpiC) were cultured to analyze the inhibitory effects of IL-34 on CP-induced TEC apoptosis.Results
Compared to vehicle treatment, anti-IL-34 Ab treatment significantly suppressed the intra-renal expression of IL-34 and its two receptors, cFMS and PTP-?, and significantly improved renal function, ameliorated tubulointerstitial injury, suppressed macrophage infiltration, and reduced apoptotic cell numbers in CP-N mice. It also significantly reduced the renal transcript levels of Kim-1, MIP-1/CCL3, TNF-?, and Bax in CP-N mice. Furthermore, anti-IL-34 Ab-treated CP-N mice showed less renal infiltration of F4/80+TNF-?+ cells. In vitro, stimulation with CP induced the expression of IL-34 and its two receptors in MRPTEpiC. Anti-IL-34 Ab treatment significantly suppressed CP-induced Bax expression with the degradation of ERK1/2 phosphorylation in damaged MRPTEpiC.Conclusions
IL-34 secreted from damaged TECs appeared to be involved in the progression of CP-N. Inhibition of IL-34 with neutralizing antibody directly prevented CP-induced TEC apoptosis by inhibiting the phosphorylation of ERK 1/2. Blocking of IL-34 appears to suppress the proliferation of cytotoxic macrophages, which indirectly attenuates CP-N. Thus, IL-34 represents a potential therapeutic target for TEC injury, and the inhibition of IL-34 might have a reno-protective effect.
SUBMITTER: Wada Y
PROVIDER: S-EPMC7799787 | biostudies-literature | 2021
REPOSITORIES: biostudies-literature
Wada Yukihiro Y Iyoda Masayuki M Matsumoto Kei K Suzuki Taihei T Tachibana Shohei S Kanazawa Nobuhiro N Honda Hirokazu H
PloS one 20210111 1
<h4>Introduction</h4>Interleukin-34 (IL-34) shares a receptor (cFMS) with colony stimulating factor-1 (CSF-1), and these two ligands mediate macrophage proliferation. However, in contrast to CSF-1, the influence of IL-34 on tubular epithelial cells (TECs) injury remains unclear. We investigated the physiological effects of IL-34 on TEC damage caused by cisplatin nephrotoxicity (CP-N).<h4>Methods</h4>Mice were administered anti-mouse IL-34 antibody (anti-IL-34 Ab; 400 ng/kg) or vehicle from 1 day ...[more]