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

J Clin Invest. 2015 Aug 3;125(8):3198-214. doi: 10.1172/JCI81166. Epub 2015 Jun 29.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Kidney Injury / genetics
  • Acute Kidney Injury / metabolism*
  • Acute Kidney Injury / pathology
  • Animals
  • Epithelial Cells / metabolism
  • Epithelial Cells / pathology
  • Female
  • Interleukins / genetics
  • Interleukins / metabolism*
  • Kidney Transplantation*
  • Kidney Tubules / metabolism
  • Kidney Tubules / pathology
  • Macrophages / metabolism*
  • Macrophages / pathology
  • Mice
  • Mice, Transgenic
  • Primary Graft Dysfunction / genetics
  • Primary Graft Dysfunction / metabolism*
  • Primary Graft Dysfunction / pathology
  • Receptor, Macrophage Colony-Stimulating Factor / genetics
  • Receptor, Macrophage Colony-Stimulating Factor / metabolism
  • Renal Insufficiency, Chronic / genetics
  • Renal Insufficiency, Chronic / metabolism*
  • Renal Insufficiency, Chronic / pathology


  • Interleukins
  • interleukin-34, mouse
  • Receptor, Macrophage Colony-Stimulating Factor