SG, MB, GS, and GC reviewed the manuscript and provided critical input. cell receptors has been shown, suggesting that these MI-1061 receptorCligand relationships could be involved in the acknowledgement and killing of TECs. Thus, triggered spleen-derived murine NK cells were shown to efficiently destroy syngeneic TECs primarily through the engagement of NKG2D activating receptor by Rae-1 ligand indicated on TECs and by the use of perforin (172). Similarly to what was observed in murine models, human being NK cells display the ability to destroy TECs (HK-2 MI-1061 cell collection) exposed to hypoxia, a disorder mimicking ischemic AKI, following a connection of NKG2D receptors with MHC class I chain-related protein A (MICA), whose manifestation is definitely upregulated in human being TECs by hypoxia-inducible element-1 alpha (HIF-1) transcription element (175). One possible mechanism of MICA upregulation in hypoxic conditions entails TGF-, a cytokine playing multifunctional tasks in inflammation, injury, and tissue restoration and induced in the kidney and in TECs, following ischemic injury (176, 177). It is of note, however, that TGF- manifestation offers been shown to correlate with limitation of renal IRI, better TEC survival, and safety against NK cell-mediated killing (177, 178). Rabbit polyclonal to ACTBL2 These effects can be explained by the fact that TGF-, besides increasing MICA surface manifestation on TECs, also induces higher levels of soluble MICA, a well-known mechanism of modulation of NK cell-mediated cytotoxic activity (62, 179). In MI-1061 addition, TGF- exerts a regulatory part on NK cell function primarily through the downregulation of different activating receptors, including NKG2D and NKp30 (180, 181). In view of these findings, MI-1061 the modulation of surface and soluble MICA manifestation could represent a useful strategy to reduce renal injury. Even though mechanisms responsible for NK cell recruitment and activation in renal IRI have not been fully elucidated, a role for osteopontin (OPN) has been shown. OPN is definitely a secreted glycoprotein indicated in different immune cells, including NK cells, and exerting pro-inflammatory functions (182C184). Notably, mRNA and protein OPN manifestation is improved in the kidney shortly after IRI (185C187), and OPN offers been shown to promote ischemic kidney injury (186, 187). The part of OPN, however, is still debated since a protecting effect for OPN both in kidney IRI and in cells restoration was MI-1061 reported (188). Interestingly, it has been demonstrated that TECs display the ability to secrete high levels of OPN, which in turn can induce a rapid NK cell migration with an indirect, still undefined, mechanism, possibly involving the induction of chemokines or additional chemotactic factors able to recruit NK cells. In addition, OPN can activate NK cells and increase their cytotoxic activity against main TECs (187). More recently, the involvement of OPN in renal injury following ischemiaCreperfusion was further validated by Cen et al. in an model. This study confirmed an OPN increase following IRI, both in the mRNA and protein levels, and shown that neutralization of OPN by an anti-OPN mAb resulted in a decreased NK cell infiltration in the kidney associated with a reduced severity of renal injury, lower levels of pro-inflammatory cytokines, and decreased neutrophil infiltration (189). Interestingly, high OPN manifestation was also observed in kidney grafts, and chronic transplant kidney injury was abrogated in OPN-deficient kidney grafts after transplantation, suggesting that OPN could play a role also in kidney allograft injury (190). The search for additional TECCNK cell relationships involved in renal IRI led to the characterization of the co-stimulatory CD137CCD137.