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

Julia Menke, Yasunori Iwata, Whitney A. Rabacal, Ranu Basu, Yee G. Yeung, Benjamin D. Humphreys, Takashi Wada, Andreas Schwarting, E. Richard Stanley, Vicki Rubin Kelley

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113 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2330-2342
Number of pages13
JournalJournal of Clinical Investigation
Volume119
Issue number8
DOIs
StatePublished - Aug 3 2009

ASJC Scopus subject areas

  • Medicine(all)

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    Menke, J., Iwata, Y., Rabacal, W. A., Basu, R., Yeung, Y. G., Humphreys, B. D., Wada, T., Schwarting, A., Stanley, E. R., & Kelley, V. R. (2009). CSF-1 signals directly to renal tubular epithelial cells to mediate repair in mice. Journal of Clinical Investigation, 119(8), 2330-2342. https://doi.org/10.1172/JCI39087