CSF-1 signaling mediates recovery from acute kidney injury
Ming-Zhi Zhang, … , Amar Singh, Raymond C. Harris
Ming-Zhi Zhang, … , Amar Singh, Raymond C. Harris
Published December 3, 2012; First published November 12, 2012
Citation Information: J Clin Invest. 2012;122(12):4519-4532. https://doi.org/10.1172/JCI60363.
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Categories: Research Article Nephrology

CSF-1 signaling mediates recovery from acute kidney injury

Abstract

Renal tubule epithelia represent the primary site of damage in acute kidney injury (AKI), a process initiated and propagated by the infiltration of macrophages. Here we investigated the role of resident renal macrophages and dendritic cells in recovery from AKI after ischemia/reperfusion (I/R) injury or a novel diphtheria toxin–induced (DT-induced) model of selective proximal tubule injury in mice. DT-induced AKI was characterized by marked renal proximal tubular cell apoptosis. In both models, macrophage/dendritic cell depletion during the recovery phase increased functional and histologic injury and delayed regeneration. After I/R-induced AKI, there was an early increase in renal macrophages derived from circulating inflammatory (M1) monocytes, followed by accumulation of renal macrophages/dendritic cells with a wound-healing (M2) phenotype. In contrast, DT-induced AKI only generated an increase in M2 cells. In both models, increases in M2 cells resulted largely from in situ proliferation in the kidney. Genetic or pharmacologic inhibition of macrophage colony-stimulating factor (CSF-1) signaling blocked macrophage/dendritic cell proliferation, decreased M2 polarization, and inhibited recovery. These findings demonstrated that CSF-1–mediated expansion and polarization of resident renal macrophages/dendritic cells is an important mechanism mediating renal tubule epithelial regeneration after AKI.

Authors

Ming-Zhi Zhang, Bing Yao, Shilin Yang, Li Jiang, Suwan Wang, Xiaofeng Fan, Huiyong Yin, Karlton Wong, Tomoki Miyazawa, Jianchun Chen, Ingrid Chang, Amar Singh, Raymond C. Harris

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Figure 2

DT induced AKI in Ggt1 DTR mice.

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DT induced AKI in Ggt1 DTR mice. (A) DT induced concentration-dependen...
(A) DT induced concentration-dependent increases in BUN in Ggt1 DTR mice (n = 4–6). (B) Representative histological photomicrographs demonstrating that renal injury (arrows) was more severe in mice 1 week after injection with 1,000 ng/kg DT than with 100 ng/kg DT. After 2 weeks, renal injury was still evident in mice with 1,000 ng/kg, but not 100 ng/kg, DT. Original magnification, ×100. (C) DT induced rapid and transient increases in cleaved caspase-3 and caspase-9 expression in Ggt1 DTR mouse kidney. (D) DT induced tubule epithelial apoptosis (TUNEL staining) in Ggt1 DTR mouse kidney, which peaked at day 2 and was decreased by 5 days after administration. Recovery from DT-mediated apoptosis was attenuated by macrophage/dendritic cell depletion with clodronate (*P < 0.01 vs. DT plus liposome at 5 days; n = 3 per group). Original magnification, ×250. (E) The number of Ki67+ cells increased by 2 days after DT administration and peaked 5–8 days after DT injection. Proliferation was significantly attenuated by macrophage/dendritic cell depletion (*P < 0.01 vs. baseline; †P < 0.01 vs. corresponding DT plus liposome; n = 4 per group). Original magnification, ×250.