Renal ischemia reperfusion injury (IRI) occurs after reduced renal blood flow and is a major cause of acute injury in both native and transplanted kidneys. Studies have shown diverse cell types in both the innate and the adaptive immune systems participate in kidney IRI as dendritic cells, macrophages, neutrophils, B cells, CD4+ NK+ cells, and CD4+ T cells all contribute to this form of injury. Recently, we have found that NK cells induce apoptosis in tubular epithelial cells (TECs) and also contribute to renal IRI. However, the mechanism of NK cell migration and activation during kidney IRI remains unknown. In this study, we have identified that kidney TECs express a high level of osteopontin (OPN) in vitro and in vivo. C57BL/6 OPN-deficient mice have reduced NK cell infiltration with less tissue damage compared with wild-type C57BL/6 mice after ischemia. OPN can directly activate NK cells to mediate TEC apoptotic death and can also regulate chemotaxis of NK cells to TECs. Taken together, our study’s results indicate that OPN expression by TECs is an important factor in initial inflammatory responses that involves NK cells activity in kidney IRI. Inhibiting OPN expression at an early stage of IRI may be protective and preserve kidney function after transplantation.

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Renal ischemia reperfusion injury (IRI) is a major cause of acute injury in both native and transplanted kidneys. This type of kidney injury is considered an antigen-independent inflammatory condition that involves multiple factors leading to tubular and endothelial dysfunction. We have recently found that NK cells induce apoptosis in tubular epithelial cells (TEC) and contribute to renal IRI. Kidney can express osteopontin (OPN) during injury. Therefore we examined the role OPN in NK cell function and kidney IRI. We have found that TEC expressed high levels of OPN in vitro and in vivo after injury. Kidneys in OPN-/- mice had less severity of IRI compared to wild-type mice (P<0.05). Interestingly, recombinant OPN could activate NK cells that express high levels of perforin and granzyme and could mediate TEC apoptotic death. Importantly, we have found that NK cell migrate towards OPN protein as well as OPN-producing TEC in the transwell assay. Whereas, less NK cell migration was seen towards OPN-/- TEC (P<0.01). Further more, Kidneys in OPN-/- mice had less NK cell infiltration after IRI compared to WT mice (P<0.02). Taken together, our study results support a previously unrecognized role for TEC expression of OPN in NK cell-mediated kidney injury. TEC expression of OPN promotes early kidney inflammatory and IRI, and limiting OPN expression may improve kidney function and graft survival.

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