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 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.