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 6

Renal macrophages/dendritic cells proliferated after DT administration.

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Renal macrophages/dendritic cells proliferated after DT administration. ...
(A) I/R caused rapid kidney infiltration of PKH26-labeled splenic monocytes versus sham animals (*P < 0.001 vs. sham; n = 3 per group), while kidney infiltration of PKH26-labeled splenic monocytes was comparable between vehicle- and DT-treated Ggt1 DTR mice at 3 and 5 days (2 × 106 cells/mouse i.v.; n = 5 per group). (B) With I/R injury, there was rapid and significant kidney infiltration of PKH26-labeled Ly6C+-enriched bone marrow cells compared with sham animals (*P < 0.01 vs. sham); 3 days after injury, there was a 390% increase. In DT-treated mice, PKH26-labeled Ly6C+-enriched bone marrow cells increased 90% at 3 days compared with vehicle-treated animals (*P < 0.01 vs. vehicle), significantly less than at the same time point after I/R injury (†P < 0.001, I/R vs. DT at 3 days), with no further increase at 5 days (5 × 106 cells/mouse i.v.). (C) DT administration (5 days) markedly increased reparative macrophage/dendritic cell proliferation (Ki67+F4/80hi cells), which was attenuated by macrophage/dendritic cell depletion (*P < 0.01 vs. baseline; †P < 0.01 vs. corresponding liposome group; n = 6). (D) 5 days after DT administration, macrophages/dendritic cells that were BrdU+F4/80hi markedly increased (*P < 0.01 vs. control; n = 3). (E) In response to I/R injury, both total macrophages and proliferating macrophages markedly increased as early as 1 day after injury and peaked at 3 days (*P < 0.05 vs. baseline; †P < 0.01 vs. 1 day after injury; n = 4).