CSF-1 signals directly to renal tubular epithelial cells to mediate repair in mice

• Published in: The Journal of clinical investigation 2009-08, Vol.119 (8), p.2330-2342
• Main Authors: Menke, Julia, Iwata, Yasunori, Rabacal, Whitney A, Basu, Ranu, Yeung, Yee G, Humphreys, Benjamin D, Wada, Takashi, Schwarting, Andreas, Stanley, E Richard, Kelley, Vicki R
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Apoptosis - drug effects; Biomedical research; Bone marrow; Cell proliferation; Cell Proliferation - drug effects; Control; Epithelial Cells - physiology; Fibrosis; Growth factors; Health aspects; Humans; Hypotheses; Inflammation; Ischemia; Kidney diseases; Kidney Tubules - pathology; Kidney Tubules - physiology; Kidneys; Macrophage colony stimulating factor; Macrophage Colony-Stimulating Factor - genetics; Macrophage Colony-Stimulating Factor - physiology; Macrophages - physiology; Measurement; Mice; Mice, Inbred C3H; Pathology; Prevention; Receptor, Macrophage Colony-Stimulating Factor - genetics; Regeneration; Reperfusion Injury - pathology; Reperfusion Injury - physiopathology; Risk factors
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/jci39087

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.