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IL-34 mediates acute kidney injury and worsens subsequent chronic kidney disease
Jea-Hyun Baek, … , Marco Colonna, Vicki R. Kelley
Jea-Hyun Baek, … , Marco Colonna, Vicki R. Kelley
Published June 29, 2015
Citation Information: J Clin Invest. 2015;125(8):3198-3214. https://doi.org/10.1172/JCI81166.
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Research Article Nephrology

IL-34 mediates acute kidney injury and worsens subsequent chronic kidney disease

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Abstract

Macrophages (Mø) are integral in ischemia/reperfusion injury–incited (I/R-incited) acute kidney injury (AKI) that leads to fibrosis and chronic kidney disease (CKD). IL-34 and CSF-1 share a receptor (c-FMS), and both cytokines mediate Mø survival and proliferation but also have distinct features. CSF-1 is central to kidney repair and destruction. We tested the hypothesis that IL-34–dependent, Mø-mediated mechanisms promote persistent ischemia-incited AKI that worsens subsequent CKD. In renal I/R, the time-related magnitude of Mø-mediated AKI and subsequent CKD were markedly reduced in IL-34–deficient mice compared with controls. IL-34, c-FMS, and a second IL-34 receptor, protein-tyrosine phosphatase ζ (PTP-ζ) were upregulated in the kidney after I/R. IL-34 was generated by tubular epithelial cells (TECs) and promoted Mø-mediated TEC destruction during AKI that worsened subsequent CKD via 2 distinct mechanisms: enhanced intrarenal Mø proliferation and elevated BM myeloid cell proliferation, which increases circulating monocytes that are drawn into the kidney by chemokines. CSF-1 expression in TECs did not compensate for IL-34 deficiency. In patients, kidney transplants subject to I/R expressed IL-34, c-FMS, and PTP−ζ in TECs during AKI that increased with advancing injury. Moreover, IL-34 expression increased, along with more enduring ischemia in donor kidneys. In conclusion, IL-34-dependent, Mø-mediated, CSF-1 nonredundant mechanisms promote persistent ischemia-incited AKI that worsens subsequent CKD.

Authors

Jea-Hyun Baek, Rui Zeng, Julia Weinmann-Menke, M. Todd Valerius, Yukihiro Wada, Amrendra K. Ajay, Marco Colonna, Vicki R. Kelley

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Figure 1

IL-34 is increased in the kidney after I/R.

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IL-34 is increased in the kidney after I/R.
In each figure, expression i...
In each figure, expression is analyzed before and after I/R. (A) IL-34 expression in B6 TECs identified using in situ hybridization (ISH), and CSF-1 using a CSF-1 reporter mouse (lacZ under control of Csf1 promoter and first intron) stained for β-galactosidase activity (X-gal). Representative photomicrographs (n = 5). Original magnification, ×2.5; inset, ×20. Dotted lines indicate the junction between the cortex (C) and the medulla (M). (B and C) We detected expression of intrarenal IL-34 transcripts and protein using qPCR (n = 5/group) (B) and ELISA (n = 4–11/group) (C), respectively. (D) Il34 transcripts in the cortex and medulla were evaluated using qPCR (n = 5/group). *P < 0.01, **P < 0.001. Statistics analyzed using the Mann-Whitney U test. Values are means ± SEM.

Copyright © 2022 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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