Ischemia/reperfusion injury associated with kidney transplantation induces profound acute injury influences

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Ischemia/reperfusion injury associated with kidney transplantation induces profound acute injury influences early graft function and affects long-term graft outcomes. After transplantation without cold storage grafts maintained CD103? but not CD103+ GFP-negative renal dendritic cells for 10 weeks. In contrast both cell subsets disappeared from cold stored grafts which associated with a significant GFP-expressing host CD11b/c+ cell infiltration that included CD103+ dendritic cells with a TNF-α producing phenotype. These changes in graft/host dendritic cell populations were associated with progressive infiltration of host CD4+ T cells with effector/effector-memory phenotypes and IFN-γ secretion. Thus renal graft ischemia/reperfusion injury causes graft dendritic cell loss and was associated with progressive host dendritic cell and T cell recruitment. Renal resident dendritic cells might function as a protective regulatory network. functional roles of renal mononuclear phagocytes in particular DC in various kidney disease models by actively eliminating DC with liposome clodronate or using PX-866 the CD11c-DTR mouse and showed contradictory results. Renal DC are protective in cisplatin-induced acute kidney injury (19) and nephrotoxic nephritis (20). On the contrary they are proinflammatory and detrimental in obstructive nephropathy (21 22 and chronic glomerulonephritis (23-25). In the model of renal warm ischemia cell population(s) that are depleted by liposome clodronate have protective roles (26) while the same liposome clodronate-depleted population(s) or CD11c+ cells depleted in CD11c-DRT mouse are shown to be detrimental (13 27 28 These conflicting outcomes might be due to different experimental settings or functions of non-DC populations as these DC deletion methods are not completely specific for DC (21 29 30 However contradictory results in these experiments could be explained by the different roles of kidney resident DC and locally recruited systemic DC and by the difficulty to differentiate two DC populations in these studies as both populations could be influenced by the depletion methods. We hypothesized that PX-866 renal graft resident DC and infiltrating host DC might have different functional roles in acute innate and MMP7 subsequent chronic phases of renal I/R injury. Accordingly using the GFP transgenic rat KTx model the aim of this study was to understand the roles of kidney resident DC by examining the alteration of renal DC in the early and late phases of renal I/R injury and by characterizing recruited host DC and other host cells. RESULTS Two types of kidney resident DC are identified in rats To characterized PX-866 kidney resident DC na?ve rat kidney leukocytes were analyzed by flow cytometry (FCM) and immunohistochemistry (IHC). FCM of isolated renal CD45+ cells revealed that the major leukocyte population in normal kidneys was CD11b/c+ cells followed by NK cells T cells and NKT cells (Fig. 1A). IHC of na?ve kidney showed that CD11b/c+ cells form a contiguous network throughout the entire kidney interstitium (Fig. 1C upper) suggesting that these cells were relevant to renal DC as previously reported in PX-866 mice and humans (10-12 14 Further analysis of CD11b/c+ renal DC showed that they expressed CD4 CD86 and MHC class II but were negative for CD62L (Fig. 1B). Subpopulation (~10%) of CD11b/c+ renal DC also expressed CD103 which were scarcely found in the interstitium (Fig. 1C lower). These results indicate the presence of two subsets of DC predominant PX-866 CD103? CD11b/c+ and minor 103+CD11b/c+ populations in na?ve rat kidneys. Figure 1 Renal resident leukocytes in na?ve rat kidney I/R injury results in fibroinflammatory changes in kidney grafts Orthotopic syngenic KTx was conducted using GFP transgenic rats as recipients and WT as donors with static cold storage of kidney grafts for 24 hrs in UW solution (24h-CS group). Donor and recipient leukocytes in kidney grafts were analyzed with a comparison to control grafts that were transplanted immediately (no-CS group). Robust mRNA upregulation for TNF-α IL-6 iNOS and IL-10 at 3 hrs after transplantation were seen in 24h-CS grafts as we have previously reported (31-33) (Fig. 2A). In contrast no-CS grafts showed negligible mRNA levels for these mediators (Fig. 2A). In addition host neutrophil infiltration was significantly increased in 24h-CS grafts while they were.