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Nrf2 deficiency improves autoimmune nephritis caused by the fas mutation lpr. Background. 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. Methods. To investigate the mechanism whereby Nrf2 contributes to the susceptibility to autoimmune diseases, we generated nrf2−/− lpr/lpr mice. Results. 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-α (TNF-α)–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-α–mediated apoptosis. Conclusion. These results indicate that a deficiency in Nrf2 enhances TNF-α–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. [ABSTRACT FROM AUTHOR]

Nrf2 is a basic leucine zipper transcriptional activator that is essential for the coordinate transcriptional induction of various antioxidant drug-metabolizing enzymes. Numerous studies have firmly established Nrf2's importance in protection from oxidative stress and certain chemical insults. Given the protective function of Nrf2, surprisingly few studies have focused on the relationship between Nrf2 and apoptosis. Therefore, we analysed how Nrf2 influences Fas signaling using Nrf2-deficient T cells. At a concentration of 1?µg/ml, the anti-Fas antibody induced 60% of cell death in Nrf2-deficient cultured thymocytes while, using the same treatment, only 40% of Nrf2 wild-type thymocytes died (P<0.05). Nrf2 deficiency enhances the sensitivity of Fas-mediated apoptosis in T cells. Next we examined the effect of Nrf2 deficiency during hepatocellular apoptosis in vivo. In comparison to wild-type mice, Nrf2-deficient mice displayed more severe hepatitis after induction with the anti-Fas antibody or tumor necrosis factor (TNF)-a. The enhanced sensitivity to anti-Fas or TNF-a stimulation was restored by preadministration of glutathione ethyl monoester, a compound capable of passing the cell membrane and upregulating the intracellular levels of glutathione. The results indicated that Nrf2 activity regulates the sensitivity of death signals by means of intracellular glutathione levels.Oncogene (2003) 22, 9275-9281. doi:10.1038/sj.onc.1207024 [ABSTRACT FROM AUTHOR]

Abstract: Systemic lupus erythematosus (SLE) is an autoimmune disorder characterized by B cell hyperactivity leading to the production of various autoantibodies and subsequent development of glomerulonephritis, i.e. lupus nephritis. Among the principal targets of the autoantibodies produced in murine SLE are nucleic acid–protein complexes and the envelope glycoprotein gp70 of endogenous retroviruses. Recent studies have revealed that the innate receptor TLR7 plays a pivotal role in the development of a wide variety of autoimmune responses against DNA- and RNA-containing nuclear antigens, while TLR9 rather plays a protective role. In addition, the regulation of autoimmune responses against endogenous retroviral gp70 by TLR7 suggests the implication of endogenous retroviruses in this autoimmune response. Moreover, the demonstration that TLR7 is involved in the acute phase expression of serum gp70 uncovers an additional pathogenic role of TLR7 in murine lupus nephritis by promoting the expression of nephritogenic gp70 autoantigen. Clearly, the eventual identification of endogenous retroviruses implicated in murine SLE and of mouse genes regulating their production could provide a clue for the potential role of endogenous retroviruses in human SLE. [Copyright &y& Elsevier]

Abstract: MafA is a member of large Maf transcription factors and activates the insulin gene in pancreatic β-cells. Other large Maf transcription factors, MafB and c-Maf, also express and activate insulin transcription in β-cells. However, the functional relationship between MafA and other Maf proteins in β-cells has not been established. In order to suppress the function of large Maf proteins, we generated transgenic mice overexpressing MafK, which act as dominant negative protein in pancreatic β-cells. These mice showed hyperglycemia at a young age due to impairment of glucose-stimulated insulin secretion. Although the transgenic mice showed an abnormal response in the glucose tolerance test, hyperglycemia was restored in adulthood. Histological analysis revealed islet hypertrophy in adult transgenic mice. Finally, an electrophoretic gel mobility shift assay showed that the DNA-binding activity of endogenous MafA was significantly increased in the MafK transgenic mice. These results indicated that MafA may have relevance to compensatory response. [Copyright &y& Elsevier]

Background and objectives: Chronic kidney disease (CKD) patients have lower levels of physical function. Especially, leg strength is important for daily living and preventing falls. However, physical function screenings are difficult to perform at clinical sites. To find clinically useful method to evaluate physical function in predialysis CKD patients, we tried to evaluate the relationship between the ratio of serum creatinine to serum cystatin C (Cre/CysC), and knee extensor muscle strength/body weight (KEMS) which reflects their leg strength. Design, setting, participants, and measurements: We recruited 147 outpatients with CKD (87 men; mean age, 61.6 ± 9.8 years; mean eGFRcreat, 40.7 ± 12.9 mL/min/1.73m2) in this cross-sectional study. KEMS was assessed using a wire strain gauge dynamometer. Skeletal muscle mass and body fat mass were assessed by bioelectrical impedance analysis. Results: The mean value of Cre/CysC was 1.01 ± 0.18. The mean value of KEMS was 1.60 ± 0.47 Nm/kg. In multivariate linear regression analysis, skeletal muscle mass (p < 0.01), body fat mass (p < 0.01), hemoglobin (p = 0.01), and Cre/CysC (p < 0.01) was independently related to KEMS. The correlation between Cre/CysC and KEMS is stronger in high quantile of Cre/CysC. Conclusions: In predialysis CKD patients, KEMS showed lower as CKD stage advanced. Cre/CysC is significantly related to KEMS independently. Cre/CysC may be an alternative marker for leg strength in CKD patients and even more valuable to utilize in cases with high Cre/CysC. [ABSTRACT FROM AUTHOR]

Adenovirus (AdV) infection is a common complication in bone marrow/hematopoietic stem cell transplant and solid organ transplant recipients. AdV infection usually presents as hemorrhagic cystitis, but sometimes it can progress to acute kidney injury showing AdV nephritis (AdVN). We present the case of a 52‐year‐old Japanese female who had received a living kidney transplantation (KT) from her husband. At 21 months post‐KT, the patient presented with a fever, but no renal dysfunction and no abnormal urine findings. A contrast‐enhanced computed tomography (CT) scan revealed a few mass lesions with hypoperfusion in the transplanted kidney. An enhanced CT‐guided biopsy targeting one of these lesions revealed a necrotizing tubulointerstitial nephritis suggesting AdVN. The polymerase chain reaction tests for ADV were negative in a urine sample but positive in the sera and the frozen kidney biopsy samples. AdVN can manifest as an unusual pattern of acute lobar nephritis/acute focal bacterial nephritis‐like localization without symptoms of acute kidney injury or urinary tract infection. Enhanced CT can provide clues for clinical diagnosis. [ABSTRACT FROM AUTHOR]

The glomerular filtration barrier is composed of podocytes, glomerular basement membrane, and endothelial cells. Disruption of these structures causes several glomerular injuries, such as focal segmental glomerulosclerosis (FSGS). The surface of podocyte apical membranes is coated by negatively charged sialic acids on core 1-derived mucin-type O -glycans. Here, we aimed to investigate the physiological role of core 1-derived O -glycans in the podocytes using adult mice lacking podocyte-specific core 1-derived O -glycans (iPod-Cos). iPod-Cos mice exhibited early and transient proteinuria with foot process effacements and developed typical FSGS-like disease symptoms. To identify the key molecules responsible for the FSGS-like phenotype, we focused on podocalyxin and podoplanin, which possess mucin-type O -glycans. Expression and localization of podocalyxin did not change in iPod-Cos glomeruli. Besides, western blot analysis revealed significantly lower levels of intact podocalyxin in isolated glomeruli of iPod-Cos mice, and high levels of processed forms in iPod-Cos glomeruli, as compared to that in control glomeruli. Conversely, podoplanin mRNA, and protein levels were lower in iPod-Cos mice than in control mice. These results demonstrated that core 1-derived O -glycan on podocytes is required for normal glomerular filtration and may contribute to the stable expression of podocalyxin and podoplanin. • Podocyte-specific Cosmc -deficient mice showed FSGS-like phenotype. • Cosmc -KO podocytes exhibited temporarily impaired glomerular filtration barrier. • Effacement of podocyte foot processes occurred in Cosmc -KO mice. • Hypoglycosylated podocalyxin and podoplanin were degraded on podocytes. [ABSTRACT FROM AUTHOR]

The transcription factor, MafB, plays important role in the differentiation and functional maintenance of various cells and tissues, such as the inner ear, kidney podocyte, parathyroid gland, pancreatic islet, and macrophages. The rare heterozygous substitution (p.Leu239Pro) of the DNA binding domain in MAFB is the cause of Focal Segmental Glomerulosclerosis associated with Duane Retraction Syndrome, which is characterized by impaired horizontal eye movement due to cranial nerve maldevelopment in humans. In this research, we generated mice carrying MafB p.Leu239Pro (Mafb mt/mt ) and retrieved their tissues for analysis. As a result, we found that the phenotype of Mafb mt/mt mouse was similar to that of the conventional Mafb deficient mouse. This finding suggests that the Leucine residue at 239 in the DNA binding domain plays a key role in MafB function and could contribute to the diagnosis or development of treatment for patients carrying the MafB p.Leu239Pro missense variant. • Mafb mt/mt mice displayed abnormal development of the inner ear and kidney podocyte, similar to the MAFB mutant patients. • Mafb mt/mt mice had decreased serum PTH level, abnormal number of α- and β-cell in the pancreas, and abnormal F4/80+ macrophages. • The phenotype of Mafb mt/mt and Mafb deficient mice was similar, indicating MafB DNA binding domain critical for its function. [ABSTRACT FROM AUTHOR]

Background: Chronic kidney disease (CKD) is a major global problem and is also associated with a decreased health-related quality of life (HRQOL). The aim of this study was to evaluate measured HRQOL based on the new CKD classification including proteinuria stage, and the effect of measured HRQOL on CKD progression and clinical outcomes over a 3-year period. Methods: EuroQol (EQ-5D), a generic preference-based questionnaire, was administered to 537 CKD outpatients at the University of Tsukuba Hospital between November and December 2008. We evaluated disease progression in CKD patients including the incidence of end-stage kidney disease (ESKD), cardiovascular disease (CVD) and all-cause mortality over a 3-year follow-up period. Results: The proportions progressing to the higher stages were 32.6, 20.0, 36.6, 39.5, and 45.8 % from glomerular filtration rate (GFR) stages (G) 1-4, respectively. The proportion progressing to ESKD (G5D) was 0.7 % from G2, 3.9 % from G3b, 20.8 % from G4 and 63.4 % from G5. The incidence of CVD and/or death was 1.2, 4.6, 4.9, 5.3, 8.3 and 21.1 % from G1−G5, respectively. The quality-adjustment weights at G4-5 were significantly lower than at G1-2 and the weights at proteinuria stage (A) 3 were significantly lower than at A1-2. The quality-adjustment weights of patients with events such as 50 % estimated GFR decline, dialysis, CVD, and/or death were significantly lower than those without events. Conclusion: We showed CKD progression and clinical outcomes over a 3-year period. Quality-adjustment weights in CKD patients were associated with not only disease progression such as initiation of dialysis treatment and incidence of CVD events and all-cause death, but also the level of proteinuria at baseline. [ABSTRACT FROM AUTHOR]

Purpose: Cisplatin is one of the most potent chemotherapeutic agents used to treat cancer. However, cisplatin-induced nephrotoxicity, which is partly caused by oxidative damage, is a serious problem. We previously showed that murine embryonic fibroblasts deficient in Peroxiredoxin I (Prx I), a major Nrf2-linked anti-oxidant enzyme, are susceptible to cisplatin-induced cytotoxicity. In the present study, we examined the role of Prx I against cisplatin-induced renal injury in vivo using Prx I-null mice. Methods: Prx I-null mice and wild-type (WT) mice were given an intraperitoneal injection of cisplatin, and tissues were removed and evaluated histopathologically. In addition, gene and protein expression of efflux transporters was analyzed. Results: In contrast to an in vitro cell study, Prx I-null mice exhibited less cisplatin-induced renal damage than WT mice in histological and blood biochemical analyses. Moreover, Prx I-null mice showed a higher clearance rate of cisplatin than WT mice following intraperitoneal cisplatin injection. Consistent with these results, Prx I-null mice exhibited higher expression of renal efflux transporters Mrp2 and Mrp4 compared with WT mice under both basal and the cisplatin-induced conditions. We suggest the enhanced transcriptional activity of c-Myc in Prx I-null mice may partly contribute the enhanced expression of renal efflux transporters. Conclusion: In summary, the enhanced clearance rate of cisplatin significantly attenuates nephrotoxicity in Prx I-null mice. [ABSTRACT FROM AUTHOR]

Abstract: Atherosclerosis is the major etiology underlying myocardial infarction and stroke, and strategies for preventing atherosclerosis are urgently needed. In the context of atherosclerosis, the deletion of the Nrf2 gene, which encodes a master regulator of the oxidative stress response in mammals, reportedly attenuates atherosclerosis formation. However, the precise mechanisms of protection against atherosclerosis are largely unknown. To further clarify the role of Nrf2 in atherosclerosis in vivo, we performed a time course analysis of atherosclerosis development utilizing an ApoE knockout (KO) mouse model. The results demonstrate that oil red O-stainable lesions were similar in size 5 weeks after the initiation of an HFC (high fat and high cholesterol) diet, but the lesions were markedly attenuated in the Nrf2 and ApoE double KO mice (A0N0 mice) compared with the lesions in the ApoE KO mice (A0N2 mice) at 12 weeks. Consistent with these results, the immunohistochemical analysis revealed that Nrf2 activation is observed in late-stage atherosclerotic plaques but not in earlier lesions. The RT-qPCR analysis of 12-week atherosclerotic plaques revealed that Nrf2 target genes, such as Ho-1 and SLPI, are expressed at significantly lower levels in the A0N0 mice compared with the A0N2 mice, and this change was associated with a decreased expression of macrophage M1-subtype genes Arginase II and inducible NO synthase in the A0N0 mice. Furthermore, the bone marrow (BM) transplantation (BMT) analysis revealed that the Nrf2 activity in the BM-derived cells contributed to lesion formation. Therefore, our study has characterized the positive role of Nrf2 in the BM-derived cells during the development of atherosclerosis, which suggests that Nrf2 may influence the inflammatory reactions in the plaques. [Copyright &y& Elsevier]

Renal involvement is a significant complication of multicentric Castleman's disease (MCD) and various glomerular involvements have been reported. A 45-year-old Japanese man presented with persistent proteinuria, with lymphadenopathy and hypergammaglobulinemia. He had been diagnosed 4 years previously with MCD. As his renal impairment had progressed to renal failure, he underwent a renal biopsy. Histology revealed diffuse and global membranous lesions with large and heterogeneous epimembranous deposits. In addition, mesangial cell proliferation and focal extracapillary lesions were found. Under immunofluorescence, granular staining for anti-IgG, IgG1, IgG2 and IgA was strongly positive in the capillary loop, and weakly positive in the mesangium. As such, there was a diversity of histological features. Our perspective with regard to pathogenesis is that the formation of the immune-complex contributed to the membranoproliferative glomerulonephritis type 3-like lesion. This histological multiform with MCD is valuable for increasing our understanding of the mechanism for onset of immune-complex glomerular deposition and cellular proliferation of glomerulonephritis. [ABSTRACT FROM AUTHOR]

MafB is a member of the large Maf family of transcription factors that share similar basic region/leucine zipper DNA binding motifs and N-terminal activation domains. Although it is well known that MafB is specifically expressed in glomerular epithelial cells (podocytes) and macrophages, characterization of the null mutant phenotype in these tissues has not been previously reported. To investigate suspected MafB functions in the kidney and in macrophages, we generated mafB/green fluorescent protein (GFP) knock-in null mutant mice. mafB homozygous mutants displayed renal dysgenesis with abnormal podocyte differentiation as well as tubular apoptosis. Interestingly, these kidney phenotypes were associated with diminished expression of several kidney disease-related genes. In hematopoietic cells, GFP fluorescence was observed in both Mac-1- and F4/80-expressing macrophages in the fetal liver. Interestingly, F4/80 expression in macrophages was suppressed in the homozygous mutant, although development of the Mac-1-positive macrophage population was unaffected. In primary cultures of fetal liver hematopoietic cells, MafB deficiency was found to dramatically suppress F4/80 expression in nonadherent macrophages, whereas the Mac-1-positive macrophage population developed normally. These results demonstrate that MafB is essential for podocyte differentiation, renal tubule survival, and F4/80 maturation in a distinct subpopulation of nonadherent mature macrophages. [ABSTRACT FROM AUTHOR]

Abstract: Transcription factor MafA is a key molecule in insulin secretion and the development of pancreatic islets. Previously, we demonstrated that some of the MafA-deficient mice develop overt diabetes mellitus, and the phenotype of these mice seems to be mild probably because of redundant functions of other Maf proteins. In this study, we generated hybrid transgenic mice that were MafA-deficient and also over-expressed MafK specifically in beta cells (MafA−/−MafK+). MafA−/−MafK+ mice developed severe overt diabetes mellitus within 5weeks old, and showed higher levels of proteinuria and serum creatinine. Histological analysis revealed that embryonic development of beta cells in the MafA−/−MafK+ mice was significantly suppressed and the reduced number of beta cells was responsible for the early onset of diabetes. Furthermore, after uninephrectomy, these mice demonstrated three characteristics of human diabetic nephropathy: diffuse, nodular, and exudative lesions. MafA−/−MafK+ mice might be a useful model for the analysis of human diabetic nephropathy. [Copyright &y& Elsevier]

A 29-year-old man with malignant lymphoma developed membranous nephropathy (MN) after allogeneic bone-marrow transplantation (BMT). There had been no obvious findings of graft versus host diseases (GVHD) after BMT, and the dosage of immunosuppressant drugs had not been reduced during this period. At the onset of MN, a few lymphoma cells still remained in the bone marrow; the patient achieved complete remission of MN after the disappearance of the lymphoma cells. In this case it is suggested that immune complexes including antigens expressed by lymphoma cells might induce MN. Therefore, this is a significant case that may reveal an alternative mechanism of the onset of MN related to BMT. [ABSTRACT FROM AUTHOR]

The transcription factor Nrf2 regulates the expression of antioxidant genes. Hyperglycemia-induced oxidative stress is involved in the pathogenesis of diabetes and its complications. However, little is known about the protective role of Nrf2 in diabetes. To gain insight into the protective role of Nrf2 in diabetes we treated Nrf2 knockout (Nrf2 KO) mice with streptozotocin (STZ). The STZ Nrf2 KO mice did not develop renal hyperfiltration, which was observed in the STZ-treated wild-type (STZ WT) mice, but renal function gradually deteriorated over the 10-week observation period. Urinary excretion of nitric oxide metabolites and the occurrence of 8-nitroguanosine, which was detected in glomerular lesions, were increased in STZ Nrf2 KO mice during the early stages after treatment. In vivo electron paramagnetic resonance analysis revealed an accelerated rate of decay of the 3-carbamoyl-2,2,5,5-tetramethylpyrrolidine-1-oxyl spin probe signal in STZ Nrf2 KO mice. The addition of superoxide dismutase prolonged the half-life of the signal, which suggested that increased oxygen radical formation occurred in the STZ Nrf2 KO mice. These results suggested that hyperglycemia increased oxidative and nitrosative stress and accelerated renal injury in the Nrf2 KO mice and that Nrf2 serves as a defense factor against some diabetic complications. [ABSTRACT FROM AUTHOR]

MafA is a transcription factor that binds to the promoter in the insulin gene and has been postulated to regulate insulin transcription in response to serum glucose levels, but there is no current in vivo evidence to support this hypothesis. To analyze the role of MafA in insulin transcription and glucose homeostasis in vivo, we generated MafA-deficient mice. Here we report that MafA mutant mice display intolerance to glucose and develop diabetes mellitus. Detailed analyses revealed that glucose-, arginine-, or KCl-stimulated insulin secretion from pancreatic β cells is severely impaired, although insulin content per se is not significantly affected. MafA-deficient mice also display age-dependent pancreatic islet abnormalities. Further analysis revealed that insulin 1, insulin 2, Pdx1, Beta2, and Glut-2 transcripts are diminished in MafA-deficient mice. These results show that MafA is a key regulator of glucose-stimulated insulin secretion in vivo. [ABSTRACT FROM AUTHOR]

The b-Zip transcription factor MafB is an essential determinant of neural development and an inducer of monocytic differentiation. The MafB protein is expressed in a variety of tissues including the developing spinal cord, retina, myelomonocytic lineages of hematopoietic cells, and peritoneal macrophages. However, the tissue-specific regulatory mechanism of mafB gene expression and its biological relevance have not been examined in detail. Here, we report, for the first time, analysis of the regulatory mechanism and tissue-specific expression of the mafB gene in vivo using transgenic mice. A transgene, containing the 8.2-kb sequence flanking the 5′ end of the mafB exon, directed the expression of a GFP reporter gene specifically in the retina, myelomonocytic lineages of hematopoietic cells, peritoneal macrophages and the ventral spinal cord. In situ hybridization analysis showed that the reporter gene expression specifically recapitulates the endogenous expression profile of mafB in the retina and spinal cord. FACS analysis revealed that the Gr-1, Mac-1 and F4/80 antigens were present on most of the GFP-positive hematopoietic cells from transgenic adult bone marrow and spleen. On the other hand, B220 CD4, 8, and Ter119 cells were almost absent from among the GFP-positive cells examined. These observations suggest that gene regulatory regions located in the 8.2-kb upstream region of mafB are responsible for directing mafB expression in the retina, myelomonocytic lineages, peritoneal macrophages and the ventral spinal cord. [ABSTRACT FROM PUBLISHER]

Mice that lack the Nrf2 (NF-E2-related factor 2) transcription factor develop a lupus-like autoimmune nephritis. The tissue-reducing activity of Nrf2-deficient mice was evaluated using a combination of real-time EPR imaging and spin probe kinetic analysis. Substantial delay in the spin probe 3-carbamoyl-2,2,5,5-tetramethylpyrrolidine-1-oxyl (Carbamoyl-PROXYL) disappearance in the liver and kidneys of Nrf2-deficient mice was observed by EPR imaging. The half-life of the spin probe in the upper abdominal area was prolonged in both the Nrf2-deficient mice and in aged mice. The combination of Nrf2 deficiency and aging in female mice resulted in the most prolonged half-life of disappearance, which was four times longer than that of juvenile female mice with a wild-type genotype. These results indicate that the low reducing activity in these organs is brought about by both Nrf2 deficiency and the aging process, and it may play a key role in the onset of autoimmune nephritis. This combination of the EPR imaging and half-life analysis appears to be a very powerful tool in the real-time analysis of reducing activity. [Copyright &y& Elsevier]

Nrf2-deficient female mice develop lupus-like autoimmune nephritis. Background. NF-E2–related factor 2 (Nrf2) is a basic leucine zipper transcriptional activator essential for the coordinate transcriptional induction of antioxidant enzymes and phase II drug metabolizing enzymes through the antioxidant response element/electrophile response element. The Nrf2-deficient 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 glomerulonephritis. The present study investigated the glomerulonephritis findings in Nrf2-deficient mice. Methods. To evaluate glomerular lesions of Nrf2-deficient mice, histological and functional analyses were performed. The amounts of serum immunoglobulins, anti-double-stranded (ds) 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 nephritis characterized by cellular proliferation, lobular formation, crescent formation, and subepithelial electron-dense deposits. In immunofluorescent assays, Nrf2-deficient female mice showed mesangial deposits and massive granular deposits of IgG, IgM, and C3 along the capillary walls. Higher serum levels of IgG, anti-dsDNA antibody, lower creatinine clearance, and slight splenomegaly also were found in Nrf2-deficient female mice. A higher concentration of TBARS also was found in Nrf2-deficient female mice. Conclusions. These data indicate that the aged Nrf2-deficient female mice develop lupus-like autoimmune nephritis and suggest that nrf2 is one of the genes determining susceptibility to autoimmune disease. Analysis of nephritis in the Nrf2-deficient female mouse may clarify the mechanisms leading to the development of lupus disease. [ABSTRACT FROM AUTHOR]