Nrf2-deficient female mice develop lupus-like autoimmune nephritis

Background. NF-E2-related factor 2 (Nrf2) is a basic leucine zipper transcr iptional activator essential for the coordinate transcriptional induction o f antioxidant enzymes and phase Il drug metabolizing enzymes through the an tioxidant response element/electrophile response element. The Nrf2-deficien t mice were found to develop normally under standard laboratory conditions, However, upon closer examination, we found that aged female Nrf2-deficient mice displayed a shortened lifespan and developed severe glomerulonephriti s. The present study investigated the glomerulonephritis findings in Nrf2-d eficient mice. Methods. To evaluate glomerular lesions of Nrf2-deficient mice, histologica l and functional analyses were performed. The amounts of serum immunoglobul ins. anti-double-stranded (cls) DNA antibody, and lipid peroxidation using thiobarbituric acid reactive substances (TBARS) also were measured. Results. Nrf2-deficient female mice over 60 weeks of age developed severe n ephritis characterized by cellular proliferation, lobular formation, cresce nt formation, and subepithelial electron-dense deposits. In immunofluoresce nt assays, Nrf2-deficient female mice showed mesangial deposits and massive granular deposits of IgG, IgM, and C3 along the capillary walls. Higher se rum levels of IgG, anti-dsDNA antibody, lower creatinine clearance, and sli ght splenomegaly also were found in Nrf2-deficient female mice. A higher co ncentration of TBARS also was found in Nrf2-deficient female mice. Conclusions. These data indicate that the aged Nrf2-deficient female mice d evelop lupus-like autoimmune nephritis and suggest that nrf2 is one of the genes determining susceptibility to autoimmune disease. Analysis of nephrit is in the Nrf2-deficient female mouse may clarify the mechanisms leading to the development of lupus disease.