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 5

Markers of M1 and M2 macrophages in kidney of AKI.

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Markers of M1 and M2 macrophages in kidney of AKI. (A) M1 markers (iNOS ...
(A) M1 markers (iNOS and Ccl3) were increased by 18 hours after initiation of I/R injury (*P < 0.05 vs. sham; n = 4), while M2 markers were elevated after 72 hours (*P < 0.01 vs. sham; n = 4). (B) In Ggt1 DTR mice, DT led to early increases in mRNA levels of the M2 markers Arg1, Igf2r, and Il4ra, which were markedly reduced by macrophage/dendritic cell depletion. Expression of M1 markers (iNOS, Ccl3, and Il23a) was not affected by clodronate treatment. White bars, liposome vehicle; black bars, clodronate (*P < 0.01 vs. control; **P < 0.01 vs. corresponding liposome group; n = 3–5). (C) Macrophage/dendritic cell depletion led to attenuated but persistent increases in Tgfb mRNA levels (*P < 0.01 vs. control; **P < 0.01 vs. corresponding liposome group; n = 3–5). (D) Pharmacologic (clodronate) or genetic (Ggt1/CD11c DTR) depletion of macrophages/dendritic cells had no effect on the mRNA levels of iNOS, Ccl3, and Il23a, but significantly reduced mRNA levels of Arg1 and Igf2r, in isolated macrophages/dendritic cells from kidneys after DT administration for 4 days (*P < 0.01 vs. control; **P < 0.01 vs. corresponding liposome group; n = 3–5). (E) Western analysis indicated increased levels of arginase (Arg), MR, and IL-4Rα in response to DT administration, which were reduced by macrophage/dendritic cell depletion.