Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0033687 (proteinuria)
 24,015 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Minimal change nephrosis (MCN) is characterized by massive proteinuria and ultrastructural alterations of glomerular visceral epithelial cells (GVEC). MCN has been associated with elevated production of interleukin (IL)-13 by circulating T lymphocytes and with T helper 2 lymphocyte-dependent conditions. We recently showed that GVEC express IL-4 and IL-13 receptors and that IL-4 and IL-13 increase transcellular ion transport over GVEC monolayers. We therefore hypothesized that IL-13 may directly injure GVEC. Here we demonstrate that IL-4 and IL-13 induce bafilomycin A1-sensitive basolateral proton secretion by cultured GVEC, indicating involvement of vacuolar H(+)-ATPase. The effects of IL-4 and IL-13 were accompanied by redistribution of the small GTPases Rab5b and Rab7, as shown by confocal immunofluorescence studies. Furthermore, Western blot analysis and assays for cysteine proteinase activity revealed basolateral secretion of the lysosomal proteinase procathepsin L by cultured GVEC, stimulated by IL-4 and IL-13. We speculate that IL-4 and IL-13 influence intracellular trafficking of proteins and promote proteolysis at the basolateral surface of GVEC, which may play a pathogenic role in altered glomerular permeability.
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PMID:Interleukin-4 and -13 promote basolateral secretion of H(+) and cathepsin L by glomerular epithelial cells. 1173 9

Sairei-to, one of the Japanese-Chinese herbal medicines has been used for the treatment of various diseases, especially collagen disease and edema in nephrotic syndrome. However, the mechanism of the therapeutic effects remains uncertain. Therefore, we investigated the immunological changes of skin, kidney, spleen cells and serum in autoimmune-prone MRL/lpr, MRL/n and C57BL/6J mice treated with Sairei-to. In MRL/lpr mice treated with Sairei-to, the improvement of proteinuria, reduction in the number of hematoxylin bodies in kidney, and reduced serum levels of blood urea nitrogen were observed. These results indicate that Sairei-to can improve or inhibit the progression of lupus nephritis. The proportion of CD19 and the serum levels of IgG1, which is one of the pathogenesis of lupus dermatoses and lupus nephritis, were significantly reduced in Sairei-to-treated MRL/lpr mice. Therefore, it is suspected that the B cell function was suppressed by Sairei-to. In addition, CD4/8 ratio in spleen cells and the degree of lymphoproliferation in MRL/lpr mice also decreased. Interestingly, IL-4 producing spleen cells were increased significantly by ELISPOT assay, and IFN-gamma mRNA expressions were reduced in Sairei-to-treated MRL/lpr mice. Regarding the Th balance, an imbalance towards Th1 predominance may play a significant role in MRL/lpr mice, and the Th1 axis was suppressed and the Th2 axis became predominant in Sairei-to-treated MRL/lpr mice. On the other hand, Th2 cell type immunoglobulins (IgG1) were suppressed. These results suggested that Sairei-to is potential for impairing shifted Th1/Th2 balance and hypergammaglobulinemia resulting in therapeutic effects.
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PMID:Unique therapeutic effects of the Japanese-Chinese herbal medicine, Sairei-to, on Th1/Th2 cytokines balance of the autoimmunity of MRL/lpr mice. 1191 7

Two peptides based on the complementarity-determining regions (CDR) 1 and 3 (pCDR1 and pCDR3) of a murine monoclonal anti-DNA autoantibody that expresses the common idiotype 16/6Id were shown to down-regulate systemic lupus erythematosus (SLE)-associated T cell responses and to prevent the development of clinical symptoms in the SLE-prone mice, (NZB x NZW)F(1). In the present study the ability of the CDR-based peptides to treat an already established disease was tested. Mice were given 10 weekly injections of peptides either i.v. or s.c. The treatment led to a moderate reduction in the anti-DNA autoantibody titer, and a significant decrease in proteinuria and kidney pathology. The CDR-based peptides affected the pathogenic isotypes (IgG2a and IgG3) of the anti-DNA antibodies in the serum and in immune complexes in the kidneys. Both peptides mitigated disease manifestations and prolonged the survival of mice that were treated starting at the age of 7 months when full-blown disease was already developed. Furthermore, some beneficial effects of treatment with the CDR-based peptides could be adoptively transferred to diseased recipients. A reduction in the secretion of IL-2, IFN-gamma, IL-4 and IL-10 was detected in supernatants of splenocytes of the treated mice. In contrast, treatment up-regulated the immunosuppresive cytokine-transforming growth factor-beta. Thus the ameliorating effect of the CDR-based peptides on SLE manifestations is at least partially via the immunomodulation of the cytokine profile.
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PMID:Peptides based on the complementarity-determining regions of a pathogenic autoantibody mitigate lupus manifestations of (NZB x NZW)F1 mice via active suppression. 1257 50

A T helper 1 (Th1)/Th2 imbalance is thought to contribute to the pathogenesis of autoimmune diseases. The differentiation of T cells into Th1 or Th2 subtypes is under the regulation of several transcription factors. Among these, transcription factor GATA-3 is thought to play an indispensable role in the development of T cells and the differentiation of Th2 cells. To examine how a Th1/Th2 imbalance affects the development of autoimmune disease, GATA-3 was overexpressed in the T lymphocytes of C57BL/6 x BXSB/MpJ-Yaa F(1) (Yaa) mice. Yaa mice developed autoimmune nephritis similarly to BXSB/MpJ-Yaa mice, which are commonly used as a model for Th1-dominant murine lupus. GATA-3 overexpression in T cells improved the 50% mortality incidence time for GATA-3-transgenic Yaa mice (41.6 wk), compared with Yaa mice (30.9 wk), and reduced proteinuria, serum creatinine levels, and the severity of glomerulonephritis in GATA-3-transgenic Yaa mice. GATA-3 overexpression in Yaa mice led to simultaneously elevated Th2 Ig (IgG1) and decreased Th1 Ig (IgG2a and IgG3) production and serum IFN-gamma levels. Although IL-4 production remained unchanged, intracellular cytokine analyses demonstrated that IL-5 was induced and IFN-gamma was suppressed in stimulated T cells from the GATA-3-transgenic Yaa mice. These results indicated that abundant GATA-3 was unable to stimulate complete differentiation of Th2 cells but did counteract the dominance of Th1 cells and alleviated the disease severity in Yaa mice. These data suggest that transcriptional regulation therapy may have potential as an effective strategy for treating autoimmune glomerulonephritis.
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PMID:Transgenic overexpression of GATA-3 in T lymphocytes improves autoimmune glomerulonephritis in mice with a BXSB/MpJ-Yaa genetic background. 1451 27

The T-helper 1/T-helper 2 (Th1/Th2) cell balance was examined in 6-month-old New Zealand black/white F1 (B/WF1) mice treated with an immunosuppressive agent, FK506. The survival rate of mice treated with 10 mg/kg/day of FK506 was 7/8, while that of those treated with 2.5 mg/kg/day was 5/8, and 4/8 after treatment for 8 weeks with placebo. Proteinuria, which was already positive in all mice before the treatment, in the seven of eight mice treated with 10 mg/kg/day remained mildly positive (< or = 1+), while seven of eight mice treated with 2.5 mg/kg/day and six of eight mice treated with the placebo showed severe proteinuria (> or = 2+). Pathological changes in the kidneys of mice treated with 10 mg/kg/day of FK506 were less severe than in mice treated with the placebo or 2.5 mg/kg/day of FK506. Expression of mRNA was unchanged for all cytokines determined in the groups treated with 2.5 mg/kg/day of FK506 or placebo. In contrast, expression of mRNA for interleukin (IL)-2, and interferon (IFN)-gamma was suppressed, while that for IL-4 and IL-10 was not suppressed in the group treated with 10 mg/kg of FK506. The serum levels of IgG-class anti-DNA antibodies, which had been elevated before the treatment, were suppressed--especially in the IgG2a subclass--and the deposition of IgG2a and IgG2b in the glomeruli was reduced in the group treated with 10 mg/kg/day of FK506 compared with the other groups. These findings suggest that an improvement in the lupus nephritis of 6-month-old B/WF1 mice induced by FK506 might be associated with a predominant inhibition of Th1 cytokine.
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PMID:Predominant inhibition of Th1 cytokines in New Zealand black/white F1 mice treated with FK506. 1516 12

IL-13 is produced by T helper 2 (Th2) cells, has a role in stimulating Th2-mediated injury, alters humoral responses, and may directly suppress macrophage and neutrophil function. In immune renal disease, the engagement of different effector mediator systems, including humoral and cell-mediated effectors, can result in glomerular injury. Experimental crescentic glomerulonephritis (known as autologous anti-glomerular basement membrane glomerulonephritis) induced by planting an antigen in glomeruli of mice is Th1 directed, delayed-type hypersensitivity (DTH)-like, and antibody independent. To test the hypothesis that, like the counterregulatory Th2 cytokines IL-4 and IL-10, endogenous IL-13 limits effector Th1 responses in glomerulonephritis, crescentic glomerulonephritis was induced in IL-13+/+ and IL-13-/- mice. Although IL-13-/- mice developed increased serum antigen-specific antibody levels, increased glomerular antibody deposition and enhanced switching to the Th1-associated IgG2a subclass, they developed a similar degree of crescentic glomerulonephritis, with similar glomerular T cell/macrophage numbers, renal impairment, and proteinuria. Antigen-specific dermal DTH and IFN-gamma production by antigen-stimulated splenocytes was unaltered. In immune complex (apoferritin-induced) glomerulonephritis, where renal injury is humorally mediated, IL-13-/- mice developed enhanced humoral immune responses and increased proteinuria, with increased IgG2a responses, a more peripheral distribution of immune complexes, but no alterations in leukocyte recruitment. These results demonstrate dissociation of IL-13's effects in antigen induced renal disease with little effect on cellular responses but suppressive effects on humoral effectors and switching to IgG2a. They indicate a role for IL-13 in limiting antibody-mediated renal injury, but not in regulating DTH-like cell-mediated responses in the kidney.
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PMID:Endogenous IL-13 limits humoral responses and injury in experimental glomerulonephritis but does not regulate Th1 cell-mediated crescentic glomerulonephritis. 1533 86

The potential physiological mechanisms explaining an influence of psychosocial stress on autoimmune diseases remain undetermined. Exposure of chronic social isolation stress to MRL/lpr mice significantly enhanced the degree of proteinuria after 20 weeks of age and reduced the survival rate. The serum anti-dsDNA IgG2a levels were increased significantly by stress at 19 weeks of age, which was simultaneously accompanied by inhibition of the serum corticosterone elevation. Furthermore, stress caused increased IFN-gamma production from anti-CD3-stimulated splenic mononuclear cells, whereas IL-4 and IL-10 production decreased. These results indicated that isolation stress exacerbated autoimmune disease in MRL/lpr mice, the possible mechanism for which might be related to stress-induced dysregulation of Th1/Th2 balance and inhibition of the blood corticosterone response to inflammatory stimuli.
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PMID:Social isolation stress exacerbates autoimmune disease in MRL/lpr mice. 1558 47

Corticosteroids are highly effective anti-inflammatory or immunosuppressive drugs used commonly to treat human systemic lupus erythematosus (SLE). All-trans-retinoic acid (ATRA), which belongs to a class of retinoids that exert immunomodulatory and anti-inflammatory functions, can also suppress the development of lupus nephritis in an animal model. However, both agents can inflict serious adverse effects. Here, we have asked whether ATRA can serve as a steroid-sparing drug in the treatment of lupus nephritis. To examine the efficacy of combining predonisolone (PSL) with ATRA, we treated intraperitoneally New Zealand black/white F1 (NZB/W F1) mice with PSL, ATRA or both agents. Survival rate and proteinuria were determined once a month. Cytokine and anti-DNA antibody production were determined by enzyme-linked immunosorbent assay (ELISA) and reverse transcription-polymerase chain reaction (RT-PCR). Renal histopathology was observed by haematoxylin and periodic acid Schiff (PAS), immunoperoxidase and immunohistochemical assay. Survival rate and proteinuria were improved in all experimental groups, and were much improved in the mice receiving the combination of ATRA and PSL (P <0.05). A single administration of ATRA reduced the Th1 [interleukin (IL)-2, interferon (IFN)-gamma and IL-12], and a Th2 (IL-4) cytokine level, as effectively as administration of PSL. ATRA also suppressed the expression of inducible nitric oxide synthetase (iNOS) and monocyte chemoattractant protein-1 (MCP-1) in the kidney. The combination of PSL and ATRA significantly reduced IgG2 (especially IgG2b)-specific anti-DNA antibody levels in comparison with administration of either agent alone. These data suggest that ATRA might have the potential to act as a new therapeutic and steroid-sparing drug against lupus nephritis.
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PMID:The beneficial effects of treatment with all-trans-retinoic acid plus corticosteroid on autoimmune nephritis in NZB/WF mice. 1560 16

Systemic lupus erythematosus is a systemic autoimmune disease characterized by inflammation in organs such as kidneys and presence of autoantibodies against nuclear antigens. We have previously shown that CD1d deficiency in BALB/c mice exacerbates lupus nephritis and autoantibody production induced by the hydrocarbon oil pristane. Here, we have tested the impact of activating CD1d-restricted natural killer T (NKT) cells on pristane-induced lupus-like autoimmunity in BALB/c and SJL mice. Repeated in vivo treatment of pristane-injected BALB/c mice with the NKT cell ligand alpha-galactosylceramide (alpha-GalCer) prior to the onset of florid disease suppressed proteinuria, in a manner that was dependent on CD1d and IL-4 expression. In sharp contrast, however, similar treatment of pristane-injected SJL mice with alpha-GalCer resulted in increased proteinuria. Consistent with these dichotomous effects of NKT cell activation on the development of lupus-like autoimmunity, NKT cells in BALB/c and SJL/J mice exhibited a mixed Th1/Th2 and a Th1-biased cytokine production profile, respectively. These findings demonstrate that NKT cell activation with alpha-GalCer suppresses or promotes pristane-induced lupus-like autoimmunity in mice, in a strain-dependent manner.
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PMID:The natural killer T cell ligand alpha-galactosylceramide prevents or promotes pristane-induced lupus in mice. 1576 49

B cell susceptibility to Fas-mediated apoptosis is downmodulated by engagement of IL-4 and sIg receptors. IL-4 produces Fas-resistance in both normal and tolerant B lymphocytes and has been associated with autoantibody production in mice expressing heterogeneous B cell receptors. To study the in vivo effects of IL-4 on autoreactive B cells in a more well-defined system, mice triply transgenic for IL-4, soluble HEL and anti-HEL B cell receptors were generated. Anti-HEL/sHEL/IL-4 triple transgenic mice matured normally but accumulated increasing amounts of serum anti-HEL antibodies over time, whereas anti-HEL/sHEL double transgenic mice lacked serum anti-HEL. Autoantibodies in triple transgenic mice were accompanied by gross evidence of renal pathology, characterized by both abnormal histology and marked proteinuria, along with microscopic evidence of immune complex-type hepatic damage. Proteinuria and histopathological changes were also observed in IL-4 transgenic control mice. These results suggest that IL-4 induced a breakdown in tolerance and autoreactive B cell activity manifested by the onset and accumulation of autoantibodies and the development of frank autoimmune disease.
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PMID:Interleukin-4 produces a breakdown of tolerance in vivo with autoantibody formation and tissue damage. 1576 19


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