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

Macrophages (M empty set) are integral in ischemia/reperfusion injury-incited (I/R-incited) acute kidney injury (AKI) that leads to fibrosis and chronic kidney disease (CK13). IL-34 and CSF-1 share a receptor (c-FMS), and both cytokines mediate M empty set 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, M empty set-mediated mechanisms promote persistent ischemia-incited AKI that worsens subsequent CKD. In renal I/R, the time-related magnitude of M empty set-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 zeta (PTP-zeta) were upregulated in the kidney after I/R. IL-34 was generated by tubular epithelial cells (TECs) and promoted M empty set-mediated TEC destruction during AKI that worsened subsequent CKD via 2 distinct mechanisms: enhanced intrarenal M empty set 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-zeta 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, M empty set-mediated, CSF-1 nonredundant mechanisms promote persistent ischemia-incited AKI that worsens subsequent CKD.