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.
View: Text | PDF
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

×

Figure 5

CSF-1 autocrine/paracrine regulated proliferation of human TECs.

Options: View larger image (or click on image) Download as PowerPoint
CSF-1 protects TECs by dampening apoptosis following injury. (A) CSF-1 s...
(A) Left panel: CSF-1 mediates HK2 TEC proliferation. CSF-1 stimulates proliferation of human HK2 TECs. Right panel: anti–CSF-1R Abs suppress CSF-1–mediated HK2 TEC proliferation. MTT assay. (B) Left panel: TEC injury increases TEC secretion of CSF-1. Following exposure of cultured HK2 TECs to increasing concentrations of actinomycin D (act-D) for 72 hours, we analyzed CSF-1 in the supernatant by ELISA. Right panel: anti–CSF-1R Abs inhibit TEC survival/proliferation in response to TEC injury. HK2 TECs were incubated with the indicated concentrations of actinomycin D in the presence and absence of anti–CSF-1R Abs for 72 hours prior to determination of cell mass by MTT assay. (C) CSF-1 expression, CSF-1R expression, and proliferation of TECs correlate in human transplants with tubular injury. Using serial sections of kidney biopsy specimens from patients with tubular injury and impaired renal function, we probed for CSF-1, CSF-1R, and proliferation in tubules. CSF-1R and CSF-1 are coexpressed on TECs by immunostaining. Note proliferating Ki67+ TECs in tubules coexpressing CSF-1 and CSF-1R. Right panels: CSF-1R and CSF-1 Ab specificity was verified using peptide preabsorption. Representative photomicrographs and correlation graphs. Original magnification, ×20. Data show means ± SEM. n = 8 per group. (D) CSF-1R is tyrosine phosphorylated in human transplants with tubular injury. Using serial sections of kidney biopsy specimens, we probed for CSF-1R and CSF-1R phosphorylation at Y723. CSF-1R and tyrosine-phosphorylated CSF-1R are coexpressed on TECs by immunostaining. CSF-1R and phospho-Y723 CSF-1R Ab specificity was verified using peptide preabsorption and rabbit IgG, respectively. Original magnification, ×40.