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 R. Kelley
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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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 1

CSF-1 hastens kidney repair and blocking CSF-1R hinders kidney repair following I/R.

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CSF-1 hastens kidney repair and blocking CSF-1R hinders kidney repair fo...
(A) Left panel: B6 mice were injected twice daily with either CSF-1 or PBS starting at day 1.5 following I/R until day 4.5. Right panel: B6 mice were injected daily with either CSF-1R or an irrelevant control Ab (rat IgG) starting at day 1.5 following I/R until day 4.5. Except for those shown in part E, all mice were sacrificed for analysis on day 5 following I/R. (B) Left panel: renal tubular histopathology (cortex and outer medulla) was less severe in CSF-1–injected than in PBS-injected mice. Right panel: renal tubular histopathology was more severe in CSF-1R Ab–injected than in control Ab–injected mice. Representative photomicrographs and corresponding graphs indicate the number of dilated tubules and casts in the cortex and outer medulla. (C) Left panel: fibrosis (collagen staining, sirius red) of TECs is decreased in mice receiving CSF-1 compared with those receiving PBS. Right panel: fibrosis is increased in CSF-1R Ab–injected compared with control Ab–injected mice. (D) Left panel: renal function (albuminuria, BUN) is attenuated following I/R in CSF-1–treated compared with PBS-treated B6 mice. Right panel: CSF-1R Ab treatment resulted in a rise of albuminuria. (E) Left panel: mice injected with CSF-1 compared with PBS sacrificed on days 1, 3, and 5 following I/R revealed that TEC proliferation in CSF-1–injected mice peaks and declines more rapidly than in PBS-injected mice. The number of apoptotic TECs evaluated by immunostaining for cleaved caspases-3 decreased in mice receiving CSF-1 compared with those receiving PBS. Right panel: TEC proliferation is reduced while the number of apoptotic cells is increased in CSF-1R Ab–injected compared with control Ab–injected mice. Representative photomicrographs are shown. Data show means ± SEM. Original magnification, ×40.