title: IL-34 mediates acute kidney injury and worsens subsequent chronic kidney disease.
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.forename: Jea-Hyun
authors.initials: JH
authors.lastname: Baek
authors.forename: Rui
authors.initials: R
authors.lastname: Zeng
authors.forename: Julia
authors.initials: J
authors.lastname: Weinmann-Menke
authors.forename: M Todd
authors.initials: MT
authors.lastname: Valerius
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Wada
authors.forename: Amrendra K
authors.initials: AK
authors.lastname: Ajay
authors.forename: Marco
authors.initials: M
authors.lastname: Colonna
authors.forename: Vicki R
authors.initials: VR
authors.lastname: Kelley
mesh_terms: D058186:Acute Kidney Injury / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D005260:Female; D007378:Interleukins / Q000235:genetics / Q000378:metabolism*; D016030:Kidney Transplantation; D007684:Kidney Tubules / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D055031:Primary Graft Dysfunction / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000378:metabolism; D051436:Renal Insufficiency, Chronic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology
chemical_list: D007378:Interleukins; C552364:interleukin-34, mouse; D016186:Receptor, Macrophage Colony-Stimulating Factor