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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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 2

CSF-1R expression on mouse and human TECs.

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CSF-1R expression on mouse and human TECs. (A) Left panel: mouse TECs ex...
(A) Left panel: mouse TECs express CSF-1R mRNA. CSF-1R transcript expression, normalized to GAPDH expression, determined by real-time PCR in primary cultured TECs derived from WT B6 mice and in cells of the proximal TEC line, C1. TECs from Csf1R–/– mice and a T cell line (DO11.10) served as negative controls, and WT BM macrophages and cells of the RAW 264 macrophage cell line served as positive controls. Right panel: CSF-1 upregulates TEC CSF-1R transcript expression. C1 cells were incubated with CSF-1 (100 ng/ml) for 24 hours and 48 hours. Results are representative of 3 separate experiments. Means ± SEM are shown. Bottom left panel: Primary TECs express CSF-1R protein. Primary WT BM macrophages and primary Csf1R–/– TECs served as positive and negative controls, respectively (n = 2–3 per group). Original magnification, ×40. Bottom right panel: CSF-1R protein detected in lysates of cultured primary WT TECs. Western blot of CSF-1R immunoprecipitates. WT BM macrophages (at less than one-third the amount of TEC protein) served as a positive control. (B) Left panel: CSF-1R transcript expression in cultured cells of the human proximal TEC line, HK2, determined by real-time PCR. The Jurkat T cell line, the human leukemic monocytic leukemia (U937), the human erythromyeloblastoid leukemia cell line (K562), and the human leukemic cell line (HL60), all stimulated with TPA, served as positive controls. Results are representative of 3 separate experiments. Data represent means ± SEM. Right panel: Human TECs (HK2 line) express CSF-1R protein detected by Western blotting. TPA-stimulated U937 cells and Jurkat T cells served as positive and negative controls, respectively.