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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]

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]

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]

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]

Monocytes and macrophages express the transcription factor MAFB (V-maf musculoaponeurotic fibrosarcoma oncogene homolog B) and protect against ischemic acute kidney injury (AKI). However, the mechanism through which MAFB alleviates AKI in macrophages remains unclear. In this study, we induced AKI in macrophage lineage-specific Mafb-deficient mice (C57BL/6J) using the ischemia-reperfusion injury model to analyze these mechanisms. Our results showed that MAFB regulates the expression of Alox15 (arachidonate 15-lipoxygenase) in macrophages during ischemic AKI. The expression of ALOX15 was significantly decreased at the mRNA and protein levels in macrophages that infiltrated the kidneys of macrophage-specific Mafb-deficient mice at 24 h after ischemia-reperfusion injury. ALOX15 promotes the resolution of inflammation under acute conditions by producing specialized proresolving mediators by oxidizing essential fatty acids. Therefore, MAFB in macrophages promotes the resolution of inflammation in ischemic AKI by regulating the expression of Alox15. Moreover, MAFB expression in macrophages is upregulated via the COX-2/PGE2/EP4 pathway in ischemic AKI. Our in vitro assay showed that MAFB regulates the expression of Alox15 under the COX-2/PGE2/EP4 pathway in macrophages. PGE2 mediates the lipid mediator (LM) class switch from inflammatory LMs to specialized proresolving mediators. Therefore, MAFB plays a key role in the PGE2-mediated LM class switch by regulating the expression of Alox15. Our study identified a previously unknown mechanism by which MAFB in macrophages alleviates ischemic AKI and provides new insights into regulating the LM class switch in acute inflammatory conditions., (Copyright © 2024 by The American Association of Immunologists, Inc.)

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 © 2010 Elsevier B.V. All rights reserved.)

MafA is a member of large Maf transcription factors and activates the insulin gene in pancreatic beta-cells. Other large Maf transcription factors, MafB and c-Maf, also express and activate insulin transcription in beta-cells. However, the functional relationship between MafA and other Maf proteins in beta-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 beta-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.