CSF-1 signals directly to renal tubular epithelial cells to mediate repair in mice
Julia Menke, … , E. Richard Stanley, Vicki R. Kelley
Julia Menke, … , E. Richard Stanley, Vicki R. Kelley
Published July 1, 2009
Citation Information: J Clin Invest. 2009;119(8):2330-2342. https://doi.org/10.1172/JCI39087.
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Research Article Nephrology

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

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.

Authors

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

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Figure 6

CSF-1 protects TECs by dampening apoptosis following injury.

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CSF-1 autocrine/paracrine regulated proliferation of human TECs. (A) Lef...
(A) CSF-1 suppresses TEC apoptosis induced by a 72-hour treatment of TECs with TNF-α/LPS. CSF-1 reduces TNF-α/LPS–induced TEC apoptosis assessed by flow cytometric annexin-PI analysis. Blocking the CSF-1R prevents CSF-1–mediated reduction in the number of apoptotic TECs. (B) TNF-α /LPS–injured TECs are self protective through a CSF-1–dependent mechanism that dampens TEC apoptosis. H2K cells were cultured for 72 hours in the absence of CSF-1. Blocking the CSF-1R increases TNF-α/LPS–induced TEC apoptosis. Data show means ± SEM. n = 5–6 per group.