Nrf2 deficiency improves autoimmune nephritis caused by the fas mutation lpr.

Abstract

Nrf2 is a basic leucine zipper transcriptional activator essential for the coordinate transcriptional induction of antioxidant and phase II drug metabolizing enzymes. We previously reported that Nrf2-deficient female mice develop lupus-like autoimmune nephritis (Kidney Int 60:1343-1353, 2001). The result suggested that nrf2 is a possible candidate gene in determining susceptibility to autoimmune diseases. MRL/lpr mice, defective in Fas-mediated apoptosis, develop glomerulonephritis due to the production of autoantibodies. To investigate the mechanism whereby Nrf2 contributes to the susceptibility to autoimmune diseases, we generated nrf2-/-lpr/lpr mice. Unexpectedly, the lifespan of nrf2-/-lpr/lpr female mice was markedly prolonged and these mice showed an improvement in nephritis compared to nrf2+/+lpr/lpr female mice. Immunologic abnormalities and hypergammaglobulinemia were also alleviated in nrf2-/-lpr/lpr female mice. Furthermore, lymphadenopathy was suppressed as a result of increased apoptosis. To elucidate the molecular mechanism causing a stimulation of apoptosis, we analyzed the response made by nrf2-/-lpr/lpr mice to death signals. We show that nrf2-/-lpr/lpr mice are sensitive to tumor necrosis factor-alpha (TNF-alpha)-mediated apoptosis. Since intracellular glutathione levels are decreased in Nrf2-deficient cells, it is probable that a prolonged depletion in glutathione levels leads to the enhancement in TNF-alpha-mediated apoptosis. These results indicate that a deficiency in Nrf2 enhances TNF-alpha-mediated apoptosis which in-turn ameliorates the abnormal apoptotic response that arises from a mutation in the lpr gene. Therefore, Nrf2 deficiency acts as a suppressor of the autoimmune accelerating gene lpr.