Major histocompatibility complexes are up‐regulated in glomerular endothelial cells via activation of c‐Jun N‐terminal kinase in 5/6 nephrectomy mice

Abstract

Background and PurposeThis study aims to explore the mechanism underlying the up‐regulation of major histocompatibility complex (MHC) proteins in glomerular endothelial cells in 5/6 nephrectomy mice.Experimental ApproachC57/BL6 mice were randomly allocated to sham‐operated (2K) and 5/6 nephrectomy (5/6Nx) groups. Mouse splenic lymphocytes, from either syngeneic or allogeneic background, were injected into 5/6Nx mice after total body irradiation. Human glomerular endothelial cells (HGECs) were cultured for experiments in vitro. Western blots, PCR, immunohistochemical and fluorescent staining were used, along with assays of tissue cytokines, lymphocyte migration and renal function.Key ResultsFour weeks after nephrectomy, expression of both mRNA and protein of MHC II, CD80, and CD86 were increased in 5/6Nx glomerular endothelial cells. After total body irradiation, 5/6Nx mice injected with lymphocytes from Balb/c mice, but not those from C57/BL6 mice, exhibited increased creatinine levels, indicating that allograft lymphocyte transfer impaired renal function. In HGECs, the protein levels of MHC and MHC Class II transactivator (CIITA) were increased by stimulation with TNF‐α or IFN‐γ, which promoted human lymphocytes movement. These increases were reduced by JNK inhibitors. In the 5/6Nx mice, JNK inhibition down‐regulated MHC II protein in glomerular endothelial cells, suggesting that JNK signalling participates in the regulation of MHC II protein.Conclusion and ImplicationsChronic inflammation in mice subjected to nephrectomy induces the up‐regulation of MHC molecules in glomerular endothelial cells. This up‐regulation is reduced by inhibition of JNK signalling.