CSF-1 signals directly to renal tubular epithelial cells to mediate repair in mice.
Tubular damage following ischemic renal injury is often reversible, and tubular epithelial cell (TEC) proliferation is a hallmark of tubular repair. Macrophages have been implicated in tissue repair, and CSF-1, the principal macrophage growth factor, is expressed by TECs. We therefore tested the hypothesis that CSF-1 is central to tubular repair using an acute renal injury and repair model, ischemia/reperfusion (I/R). Mice injected with CSF-1 following I/R exhibited hastened healing, as evidenced by decreased tubular pathology, reduced fibrosis, and improved renal function. Notably, CSF-1 treatment increased TEC proliferation and reduced TEC apoptosis. Moreover, administration of a CSF-1 receptor-specific (CSF-1R-specific) antibody after I/R increased tubular pathology and fibrosis, suppressed TEC proliferation, and heightened TEC apoptosis. To determine the contribution of macrophages to CSF-1-dependent renal repair, we assessed the effect of CSF-1 on I/R in mice in which CD11b+ cells were genetically ablated and determined that macrophages only partially accounted for CSF-1-dependent tubular repair. We found that TECs expressed the CSF-1R and that this receptor was upregulated and coexpressed with CSF-1 in TECs following renal injury in mice and humans. Furthermore, signaling via the CSF-1R stimulated proliferation and reduced apoptosis in human and mouse TECs. Taken together, these data suggest that CSF-1 mediates renal repair by both a macrophage-dependent mechanism and direct autocrine/paracrine action on TECs.
Menke
Julia
J
Laboratory of Molecular Autoimmune Disease, Renal Division, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.
Iwata
Yasunori
Y
Rabacal
Whitney A
WA
Basu
Ranu
R
Yeung
Yee G
YG
Humphreys
Benjamin D
BD
Wada
Takashi
T
Schwarting
Andreas
A
Stanley
E Richard
ER
Kelley
Vicki R
VR
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004847:Epithelial Cells / Q000502:physiology; D005355:Fibrosis; D006801:Humans; D007684:Kidney Tubules / Q000473:pathology / Q000502:physiology*; D016173:Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000502:physiology*; D008264:Macrophages / Q000502:physiology; D051379:Mice; D008809:Mice, Inbred C3H; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000235:genetics; D012038:Regeneration; D015427:Reperfusion Injury / Q000473:pathology / Q000503:physiopathology*
D016173:Macrophage Colony-Stimulating Factor; D016186:Receptor, Macrophage Colony-Stimulating Factor