Kidney International, Vol. 60 (2001), pp. 1606–1607

EDITORIAL

Nephritis promoted by oxidative injury

Systemic lupus erythematosus, an inflammatory dis- the development of nephritis in the NZB mouse [4].Other examples of experimental nephritis suggest thatease of unknown cause, is characterized by immunologi-overexpression of specific genes (e.g., bcl-2, IL-4) cancal injury to diverse tissues, including skin, serosal sur-attenuate lymphocyte apoptosis and impede differentia-faces, and the kidneys. Although the specific pathogenetiction toward TH1 cell-mediated immunity, thus favoringmechanisms are incompletely understood, developmentinappropriate cell survival, autoreactivity, and immuno-of the disorder appears to require polyclonal activationglobulin overproduction [5, 6]. While the genetic back-of B and T lymphocytes, production of autoantibodiesground of different murine strains contributes to thedirected against specific nuclear and cytosolic antigens,development and progression of renal diseases, the vari-and immune complex deposition [1]. In the kidney, suchous models underscore the central roles of immune cellimmune complex deposition within the glomerular mes-survival and activitation, as well as differentiation alongangium and along the subendothelial and subepithelialTH2 pathways with its associated overproduction of dis-margins of the basement membrane seems to be a criticalease-specific autoantibodies.event that sets an inflammatory cascade in motion. These

Although immune cells are key in initiating the eventsetiopathogenic mechanisms are, in turn, modulated byof immune complex renal disease, other pro-inflamma-a complex interplay of genetic, environmental, and hor-tory and remodeling pathways likely modulate the pro-monal factors that ultimately determine the spectrumgression and maturation of these lesions. For example,and severity of disease.lymphocyte activation may result in downstream effects,Our understanding of how these diverse factors con-including increased production of pro-inflammatory cyto-

tribute to disease progression has advanced in recent kines, angiogenic growth factors, and reactive oxygen spe-years through investigations with several experimental cies [7]. These later events may be the crucial regulatorsmodels that resemble, if not recapitulate, lupus. As most of matrix deposition and parenchymal scarring and couldof these are characterized by a proliferative glomerulo- ultimately turn an acute, reversible inflammatory lesionnephritis, such models are proving to be especially valu- into one of irreversible fibrosis. In this issue of Kidneyable in elucidating how specific immune defects contrib- International, Yoh et al demonstrate that targeted dele-ute to renal disease and suggest potential candidate genes tion of the basic leucine zipper protein Nrf2, a transcrip-and mechanisms for study in human nephritis. Histori- tion activator for several antioxidant enzymes, results incally, while efforts have focused on experimental murine the development of an immune complex nephritis instrains that spontaneously develop a lupus-like syn- aged female ICR mice [8]. These mice demonstrate sev-drome (e.g., NZB/W F1, MRL/lpr, and BXSB), trans- eral immunopathological features of human lupus, in-genic techniques extend these studies and identify other cluding splenomegaly, proteinuria, production of ANApathways that lead to the development of immune dys- and anti-dsDNA antibodies, mesangial and capillary de-regulation with autoreactivity and immune complex ne- position of IgG, IgM and C3 complement with subsequentphritis. Each of the models, in turn, suggests a potential proliferative/crescentic change within glomeruli, and, even-

tually, renal failure and death. These findings suggestingmechanism by which the disease evolves and allows thea role for oxidant stress in the development of lupus areunique opportunity to directly test if targeted therapiessupported by previous work by other investigators show-modulate renal survival, and how such specific defectsing that knockouts of specific antioxidant genes down-potentiate progression of other autoimmune models.stream from Nrf2 also develop a crescentic glomerulone-Targeted gene deletion of components known crucialphritis [9], as well as observations that supplementationto immune cell pathways has generated rodents withwith omega-3 fatty acids generally upregulate antioxidantautoreactivity and nephritis. Examples include defects inenzyme gene expression and ameliorate nephritis in thesrc tyrosine kinases [2] and transforming growth factor-�NZB/W model [10].(TGF-�) [3]. In addition, the blockade of tumor necrosis

However, it is important to be cautious in assumingfactor (TNF) pathways has also been shown to acceleratethe Nrf2 gene is critical to the development of lupus ne-phritis de novo, as several important features distinguishthis model from well-established “lupus-like” strains. First,Key words: systemic lupus erythematosus, B and T lymphocytes, prolif-

erative glomerulonephritis. the appearance of clinically detectable nephritis occursquite late in these animals, usually after 60 weeks of age, 2001 by the International Society of Nephrology

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Editorial 1607

much beyond the time frame demonstrated in other Correspondence to Victor M. Byrd, M.D., Vanderbilt UniversityMedical Center, Division of Rheumatology, T 3219 MCN, 21st Ave andmodels such as NZB/W and MRL/lpr. In addition, theGarland, Nashville, TN 37232, USA.

ICR strain itself shows an intrinsic predisposition toward E-mail: victor.byrd@mcmail.vanderbilt.eduthe delayed development of nephritis and produces anti-dsDNA antibodies at detectable levels [8, 11]. The likely

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and Fyn. Curr Biol 11:34–38, 2000extrapolations made from this Nrf2 model to human3. Dang H, Geiser AG, Letterio JJ, et al: SLE-like autoantibodieslupus should be made cautiously. However, as Yoh et and Sjogren’s syndrome-like lymphoproliferation in TGF-beta

al recognize, the real lesson may be that the repair and knockout mice. J Immunol 155:3205–3212, 19954. Kontoyiannis D, Kollias G: Accelerated autoimmunity and lupusremodeling response to immunologically mediated tissue

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7. Grande JP: Mechanisms of progression of renal damage in lupus(e.g., antigrowth factor or antioxidant strategies). Such nephritis: pathogenesis of renal scarring. Lupus 7:604–610, 1998new perspectives may allow investigators to identify po- 8. Yoh K, Itoh K, Enomoto A, et al: Nrf2-deficient female mice

develop lupus-like autoimmune nephritis. Kidney Int 60:1343–1353,tentially damaging repair pathways in human disease and2001ultimately prevent the fibrosis and organ debilitation

9. Poss KD, Tonegawa S: Heme oxygenase 1 is required for mamma-that follows such repair. This knowledge will likely prove lian iron reutilization. Proc Natl Acad Sci 94:10919–10924, 1997

10. Chandrasekar B, Fernandes G: Decreased pro-inflammatory cy-beneficial in developing novel approaches toward othertokines and increased antioxidant enzyme gene expression bychronic inflammatory lesions, including allograft rejec-omega-3 lipids in murine lupus nephritis. Biochem Biophys Res

tion, wound repair, and rheumatoid arthritis. Comm 200:893–898, 199411. Eaton GJ, Johnson FN, Custer RP, Crane AR: The Icr:Ha (ICR)

Victor M. Byrd and James W. Thomas mouse: A current account of breeding, mutations, diseases andmortality. Lab Anim 14:17–24, 1980Nashville, TN, USA