Oxidation resistance protein 1 (Oxr1) protects against autoantibody-induced glomerulonephritis by inhibiting inflammation and apoptosis (56.10)

Abstract

Abstract Oxidative stress is a common pathologic feature of immune-mediated nephritis in both human and mouse model. However, the molecular pathways that govern defense against oxidative stress-induced renal injury remain unclear. Using experimental autoantibody-induced nephritis mouse model, we have identified OXR1 may play a protective role against anti-GBM disease and lupus nephritis. Impaired expression of OXR1 was observed in the kidneys of 129/svj and DBA1 mice that suffered from severe anti-GBM-antibody induced nephritis, compared with non-disease controls. The reduced expression of OXR1 was also detected in kidneys of congenic mice with spontaneous lupus nephritis (e.g., B6.Sle1.Sle3 and B6.Mrl/Lpr). Deliberate delivery of human OXR1 via lentiviral vector into mouse kidney attenuated anti-GBM-antibody induced nephritis in 129/svj mice. The overexpression of hOXR1 in recipient mice down-regulated the expression of several inflammatory chemokines, including RANTES, SDF-1, IL1β and IL6, and suppressed the infiltration of macrophage/lymphocyte in the kidneys. The increased OXR1 was also associated with reduced renal cell apoptosis in anti-GBM mice. In vitro experiment further proved that hOXR1-transfected macrophages are more resistant to H2O2-induced apoptosis. These findings suggest that OXR1 may play a protective role in immune-mediated nephritis by modulating inflammation and oxidative stress and therefore may be a potential therapeutic target for lupus nephritis.