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Viewed by the Institutional Lab- M2mws Were Counted, and 1.03106 Viable Cells Were Suspended in Oratory Animal Care and Use Committee of Nagoya City University BASIC RESEARCH www.jasn.org Colony-Stimulating Factor-1 Signaling Suppresses Renal Crystal Formation † Kazumi Taguchi,* Atsushi Okada,* Hiroshi Kitamura, Takahiro Yasui,* Taku Naiki,* Shuzo Hamamoto,* Ryosuke Ando,* Kentaro Mizuno,* Noriyasu Kawai,* Keiichi Tozawa,* ‡ ‡ † Kenichi Asano, Masato Tanaka, Ichiro Miyoshi, and Kenjiro Kohri* Departments of *Nephro-urology, and †Comparative and Experimental Medicine, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan; and ‡Laboratory of Immune Regulation, School of Science, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan ABSTRACT We recently reported evidence suggesting that migrating macrophages (Mws) eliminate renal crystals in hyperoxaluric mice. Mwscanbeinflammatory (M1) or anti-inflammatory (M2), and colony-stimulating factor-1 (CSF-1) mediates polarization to the M2Mw phenotype. M2Mws promote renal tissue repair and regeneration, but it is not clear whether these cells are involved in suppressing renal crystal formation. We investigated the role of M2Mws in renal crystal formation during hyperoxaluria using CSF-1–deficient mice, which lack M2Mws. Compared with wild-type mice, CSF-1–deficient mice had significantly higher amounts of renal calcium oxalate crystal deposition. Treatment with recombinant human CSF-1 increased the expression of M2-related genes and markedly decreased the number of renal crystals in both CSF-1– deficient and wild-type mice. Flow cytometry of sorted renal Mws showed that CSF-1 deficiency resulted in a smaller population of CD11b+F4/80+CD163+CD206hi cells, which represent M2-like Mws. Additionally, transfusion of M2Mws into CSF-1–deficient mice suppressed renal crystal deposition. In vitro phagocytosis assays with calcium oxalate monohydrate crystals showed a higher rate of crystal phagocytosis by M2- polarized Mws than M1-polarized Mws or renal tubular cells. Gene array profiling showed that CSF-1 de- ficiency resulted in disordered M2- and stone-related gene expressions. Collectively, our results provide compelling evidence for a suppressive role of CSF-1 signaling in renal crystal formation. J Am Soc Nephrol 25: 1680–1697, 2014. doi: 10.1681/ASN.2013060675 We previously used microarray analysis to show a processing, although the mechanisms by which correlation between renal calcium oxalate (CaOx) they interact with crystals remain unclear. crystal formation and macrophages (Mws).1 We There are two subtypes of Mws, classically acti- also observed the migration of Mws to renal tubular vated (M1) and alternatively activated (M2) Mws, cells (RTCs) that include crystals followed by the which exert pro- and anti-inflammatory effects, respec- disappearance of crystals in the tubular lumen from tively.7,8 Resident tissue Mws differentiate after stimu- thecorticomedullaryjunctioninhyperoxaluric lation by various cytokines.9,10 Associations were mice.2 Mws and multinucleated giant cells also en- reported between kidney stones and atherosclerotic capsulated interstitial crystals in the kidneys of hy- peroxaluric rats and humans with acute and chronic oxalosis.3 In addition, normal rat kidney Received June 30, 2013. Accepted December 4, 2013. epithelial cells expressed monocyte chemotactic Published online ahead of print. Publication date available at protein-1 (MCP-1), the levels of which increased www.jasn.org. after exposure to CaOx monohydrate (COM) crys- Correspondence: Dr. Atsushi Okada, Department of Nephro- 4 5 tals and oxalate. Finally, several in vitro and in urology, Nagoya City University Graduate School of Medical vivo6 studies reported that urinary COM crystals Sciences, Kawasumi 1, Mizuho-cho, Mizuho-ku, Nagoya 467- couldbedegradedanddissolvedbyMws. These 8601, Japan. Email: [email protected] findingssuggestthatMwsinfluence crystal Copyright © 2014 by the American Society of Nephrology 1680 ISSN : 1046-6673/2508-1680 JAmSocNephrol25: 1680–1697, 2014 www.jasn.org BASIC RESEARCH Figure 1. Morphologic and quantitative distribution of renal CaOx crystals. (A) Representative micrographs and three-dimensional imaging of renal sections harvested on day 6. In op/op mice, renal crystal deposits were detected inside the tubular lumen, predominantly at the papilla, using Pizzolato staining and polarized light optical microphotography. Pizzolato staining showed large crystals in the intratubular space of the renal papillary region in op/op mice. Crystallization throughout the kidney tissue is observed as white dots in the renal pa- renchyma with three-dimensional CT images. Original magnification, 340; 3400 in inset. Scanning EM showed that crystals in op/op mice were disordered and large compared with those crystals in the other groups of mice. Original magnification, 33000. Scale bar: 5 mm. CSF- 1–treated groups had the same intratubular crystal formation as the untreated groups, but the crystals were more disordered when assessed by scanning EM. (B) Qualitative analysis of crystals formed by the administration of glyoxylate using x-ray diffraction. X-ray diffraction analysis showed that the major component of renal crystals in op/op mice was COM, because multiple diffraction peaks characteristic of COM and no peaks characteristic of CaOx dihydrate or other components were detected. plaques in which various types of Mw migrate.11–14 In these Some reports suggested that colony-stimulating factor-1 studies, M2Mwsinfiltrated early atherosclerotic lesions, (CSF-1) signaling mediates tissue regeneration after injury whereas M1Mws were found predominantly in advanced le- and also, alters Mw polarization to the M2 phenotype.18–20 sions. Plaque formation correlated with the dominance of the In addition, several studies21–23 have used CSF-1–deficient M1 phenotype.15 Several reports suggested that M2Mws de- (op/op)mice,24 which contain a point mutation in CSF1 creased tissue inflammation and promoted tissue healing in and exhibit fewer circulating monocytes and tissue Mws GN16 and ischemia/reperfusion kidneys.17 than mice with CSF-1. Although these studies showed that J Am Soc Nephrol 25: 1680–1697, 2014 CSF-1 Suppresses Renal Crystals 1681 BASIC RESEARCH www.jasn.org Figure 2. Quantitative estimation of renal and urinary CaOx crystals. (A) The ratio of areas with renal crystal deposition. Crystallization in each kidney section was quantified by calculating the ratio (percent) of the area containing crystals to the entire kidney section using Image Pro Plus. (B) The number of urinary crystals per high-powered field; 24-hour urine samples on days 0 and 6 were collected in a metabolic cage, and CaOx crystals were counted at 3400 magnification. Day 6 (CSF-1) indicates that all mice in each genotype group were treated with 5.0 mgCSF-1.n=6 for all time points in each group. Data are presented as means6SEMs. *P,0.05 compared † between the +/+, +/op,andop/op groups at the same time points; P,0.05 compared with day 0 in each group; §P,0.05 compared with day 6 in each group. loss of CSF-1 significantly reduces atherosclerotic severity, RESULTS they did not elucidate the role of Mw polarization in these outcomes. Morphologic and Quantitative Analysis of Renal and In this study, we examined and compared renal crystal Urinary CaOx Crystals formation and Mw polarization in wild-type and CSF-1– CaOx crystals were present predominantly in the renal tubular deficient mice after hyperoxaluric treatment. We showed lumenatthepapillainop/op mice and the renal tubular lumen at that CSF-1 deficiency results in increased renal crystal depo- the corticomedullary junction in both +/+ and +/op mice, con- sition and fewer M2-like Mws. We also found that the in vitro sistent with a previous study.25 Three-dimensional computed to- phagocytosis of COM crystals was higher in M2-polarized mography (CT) images of whole kidneys showed increased renal Mws from bone marrow-derived Mws (BMMs). Overall, this crystal deposits in op/op mice compared other groups (Figure 1A). study showed that CSF-1 suppresses renal crystal formation in Scanning electron microscopy (EM) revealed large disor- hyperoxaluric mice. dered crystals in op/op mice compared with radial ordered 1682 Journal of the American Society of Nephrology J Am Soc Nephrol 25: 1680–1697, 2014 edly higher in groups exhibited CaOx crystalluria atgroups day (Figure 6, which 2A). was After mark- CSF-1 treatment treatment with decreased glyoxylate, the all number of crystals in all creased CaOx crystalluria in expression between any groups of mice. signi COM (Figure 1B). signi were identi renal interstitium in all six groups; no signi CSF-1 treatment. There was no signi that the major component ofdisordered renal by crystals scanning in EM. X-rayobserved diffraction in analysis showed the untreatedmice groups, had but intratubular the crystals crystals comparablemice were caused with more dilation of those the crystals renal tubular lumen. CSF-1 J Am Soc Nephrol and shown in Figure 4A. and mucin-like hormone receptor The mRNA expression of EGF-likeGlyoxylate module-containing Treatment Increased F4/80 ( 0 to 6 inmarked all increase genotypes, in including the secretedQuantitative expression phosphoprotein RT-PCR of 1 several of genes whole-kidney from day tissueCSF-1 revealed a Table 1. Serum biochemistry andSerum urinary and variables Urinary Variables are shown in crystals in Mice Crystal Binding and Related Genes in rogated by CSF-1 treatment in(Figure all 3B). groups. The stainingtubular intensity epithelial cells, of predominantly in these theANX2, proteins pericrystal and region was MCP-1 ab- was observed on the
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