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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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 8

CSF-1 is essential for recovery from AKI through promoting macrophage/dendritic cell proliferation and polarization to an M2 phenotype.

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CSF-1 is essential for recovery from AKI through promoting macrophage/de...
(A) CSF-1 deficiency augmented DT-mediated AKI, as indicated by increased BUN (*P < 0.05 vs. WT; n = 6 per group) and by delayed histologic recovery (arrows) 12 days after DT administration. Original magnification, ×160. (B and C) CSF-1 deficiency markedly inhibited DT-mediated increases in total and proliferating resident macrophages/dendritic cells (*P < 0.001 vs. control; †P < 0.01 vs. WT; n = 4; B), decreased expression of M2 markers, and increased expression of M1 markers in isolated renal macrophages/dendritic cells 5 days after DT injection (*P < 0.05 vs. WT; n = 4; C). (D) CSF-1 deficiency attenuated the increases in both total and proliferating renal macrophages/dendritic cells in response to I/R injury on day 3 (*P < 0.05 vs. control; †P < 0.05 vs. WT; n = 4). (E) CSF-1 deficiency increased levels of M1 markers and decreased levels of M2 markers in isolated macrophages/dendritic cells 3 days after I/R injury (*P < 0.05, **P < 0.01 vs. WT; n = 4–6).