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)

The effector mechanisms of T cell-dependent acute glomerular injury were studied in autologous phase anti-GBM glomerulonephritis (GN) in rats. Acute proliferative GN was induced in sensitized rats by a subnephritogenic dose of sheep anti-rat GBM antibody. Injury was manifested by proteinuria and glomerular leucocyte infiltration composed predominantly of macrophages but also CD4+ and CD8+ T cells. T cell depletion, using an anti-CD5 MoAb, demonstrated that glomerular leucocyte infiltration and proteinuria were T cell-dependent. Inhibition of T helper cell function using an anti-CD4 MoAb prevented proteinuria and glomerular macrophage and CD4+ T cell influx, but not accumulation of CD8+ T cells. Depletion of CD8+ T cells also prevented proteinuria and the influx of macrophages and CD8+ T cells, but not accumulation of CD4+ T cells. Macrophage depletion, using micro-encapsulated clodronate, prevented proteinuria and glomerular macrophage infiltration, but not the accumulation of CD4+ or CD8+ T cells, indicating that macrophages are the common cellular effectors for both CD4 and CD8 T cell-dependent injury. Evidence for cytotoxic mechanisms of injury (increased numbers of apoptotic cells or accumulation of natural killer (NK) cells in glomeruli) could not be demonstrated. These data suggest that acute glomerular injury in anti-GBM GN is the result of macrophage recruitment, which is dependent on both CD4 and CD8 T cells, and that direct T cell-mediated injury (cellular cytotoxicity) is not involved.
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PMID:Mechanisms of T cell-induced glomerular injury in anti-glomerular basement membrane (GBM) glomerulonephritis in rats. 921 36

T cells with T cell receptor (TCR) transgenes that recognized CD1 on syngeneic B cells stimulated B cells to secrete immunoglobulins in vitro. The CD4+, CD8+, or CD4-CD8- T cells from the spleen of the TCR transgenic BALB/c donors induced lupus with anti-double stranded DNA antibodies, proteinuria, and immune complex glomerulonephritis in irradiated BALB/c nude mice reconstituted with nude bone marrow. Injection of purified CD4-CD8- T cells from the marrow of transgenic donors prevented the induction of lupus by the transgenic T cells. Transgenic T cells that induced lupus secreted large amounts of interferon (IFN)-gamma and little interleukin (IL)-4, and those that prevented lupus secreted large amounts of IL-4 and little IFN-gamma or IL-10.
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PMID:Subsets of transgenic T cells that recognize CD1 induce or prevent murine lupus: role of cytokines. 946 3

We investigated the effects of anti-CD4 monoclonal antibody (mAb) and/or anti-CD8 mAb in ddY mice, an animal model of spontaneous IgA nephropathy. Female ddY mice were treated with 18 intravenous injections of anti-CD4 and/or anti-CD8 mAb at 2-week intervals. This was based on our observation that a single injection of anti-CD4 mAb or anti-CD8 mAb caused a selective depletion in CD4+ T cells for 2 weeks and CD8+ T cells for 4 weeks, respectively. The level of proteinuria, serum IgA, and changes in the histopathological features of renal tissue samples were assessed in treated mice between the age of 4 and 40 weeks. The level of proteinuria increased with age, but there was not significant difference among the groups. No animal developed microhematuria throughout the study. Treatment with anti-CD4 mAb produced a mild to moderate level of mesangial hypertrophy at 20 and 40 weeks, similar to the results in untreated mice. The lowest degree of mesangial hypertrophy occurred in mice treated with anti-CD8 mAb up to the age of 40 weeks. Treatment with a combination of anti-CD4 and anti-CD8 mAbs produced effects that were similar to those observed on treatment with anti-CD8 mAb alone. Our results suggest that CD8+ T cells mediate mesangial proliferation and the progression of nephropathy in ddY mice.
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PMID:Anti-CD8 monoclonal antibody protects against spontaneous IgA nephropathy in ddY mice. 954 92

Prostacyclin (PGI2) is known to have a relaxative action on vascular smooth muscle, an inhibitory action against platelet activation and neutrophil function. Previous studies showed the preventive effects of PGI2 on lupus nephritis and Thy-1 nephritis, although the mechanism has not been clarified. Glomerular endothelial expression of intercellular adhesion molecule-1 (ICAM-1) is up-regulated in experimental and human glomerular diseases, and is known to facilitate leukocyte infiltration into the glomeruli, which ultimately induces the various glomerular injuries. In the present study, we evaluated the therapeutic effects of PGI2 on a rat model for crescentic glomerulonephritis and investigated its putative mechanism in relation to ICAM-1-mediated leukocyte recruitment. Wistar-Kyoto (WKY) rats were injected with nephrotoxic serum and received continuous intraperitoneal infusion of PGI2. PGI2 dramatically decreased proteinuria (123.0 +/- 18.8 vs. 31.6 +/- 4.5), crescent formation and deposition of fibrinogen in the glomeruli, while the deposition of rabbit IgG, rat IgG and rat C3 along the capillary walls was not changed. Furthermore, intraglomerular expression of ICAM-1 and infiltration of macrophages were significantly suppressed by administration with PGI2. In contrast, influx of CD4 or CD8 positive cells was not altered. The present results suggest that PGI2 shows the preventive effects on experimental crescentic glomerulonephritis by inhibiting intraglomerular coagulation and ICAM-1-mediated macrophage-glomerular endothelial cell adhesive pathway.
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PMID:Therapeutic effects of prostacyclin analog on crescentic glomerulonephritis of rat. 957 47

The contribution of CD4 and CD8 cells to crescentic glomerulonephritis (GN) was studied in mice genetically deficient in CD4, CD8, and with combined CD4 and CD8 (CD4/CD8) deficiency. Wild-type (C57BL/6) mice developed GN with mild proliferative changes 7 days after an intravenous dose of sheep anti-mouse glomerular basement membrane globulin. Crescents were observed in 12.5 +/- 6.1% of glomeruli on day 14. On day 21, 51.5 +/- 7.3% of glomeruli were affected by crescents, and mice had marked azotemia and proteinuria. CD4 and combined CD4/CD8-deficient mice developed minimal evidence of GN. On day 21, their glomeruli showed only mild proliferative changes and crescents, azotemia, and proteinuria were absent. In contrast, CD8-deficient mice developed severe crescentic GN with three of five mice dying on day 20 with ascites and edema. The two mice surviving to day 21 had severe azotemia. Crescent development was accelerated (day 14, 51.6 +/- 2.4% of glomeruli; day 20 or 21, 62.0 +/- 4.0% of glomeruli). These studies demonstrate that CD4 cells are crucial for the development of crescentic GN in mice and that genetic absence of CD8 cells accelerates disease. They support the hypothesis that crescent formation is a manifestation of CD4-dependent (and CD8-independent) delayed type hypersensitivity in the glomerulus.
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PMID:Crescentic glomerulonephritis in CD4- and CD8-deficient mice. Requirement for CD4 but not CD8 cells. 962 58

In the present study, we examined the preventive effect of anti-mouse IL-6 receptor (IL-6R) antibody, MR16-1, on the development of autoimmune kidney disease in female NZB/W F1 (BWF1) mice. Immunological tolerance to MR16-1 or isotype-matched control antibody, KH-5, was induced by the simultaneous administration of anti-CD4 MoAb in mice. Thereafter, mice were intraperitoneally given 0.5 mg of MR16-1, 0.5 mg of KH-5 or saline once a week from 13 to 64 weeks of age. MR16-1 treatment dramatically suppressed proteinuria and prolonged the survival time of BWF1 mice. Only one out of 10 mice died with high levels of proteinuria throughout the experiment. MR16-1 almost completely suppressed the production of IgG forms of anti-DNA and anti-TNP antibodies, but not the IgM forms of these antibodies. In particular, all IgG subclasses (IgG1, IgG2a, IgG2b and IgG3) of anti-DNA antibody production were significantly suppressed. Moreover, serum IgG1, IgG2a and IgG3 levels in MR16-1-treated mice were lower than those in saline- and KH-5-treated mice, whereas serum IgM and IgA levels were not influenced. In conclusion, MR16-1 potently suppressed the development of autoimmune disease in BWF1 mice, and this was attributed to its effect of specific suppression of IgG class antibody production.
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PMID:IL-6 receptor blockage inhibits the onset of autoimmune kidney disease in NZB/W F1 mice. 964 7

Chronic graft-vs-host (cGVH) disease induced by the transfer of Ia-incompatible spleen cells from one normal mouse strain (such as B6.C-H2(bm12)/KhEg (bm12)) to another (such as C57BL/6) causes an autoimmune syndrome resembling systemic lupus erythematosus (SLE). The role of host-derived T cells in this response is not obvious. Previous reports suggested that host T cells might serve to down-regulate the autoimmune syndrome. To address this issue more definitively, we used CD4 knockout (KO) or CD8KO C57BL/6 (B6) mice as recipients in the bm12-->C57B6 cGVH model. CD4KO B6 mice injected with allogeneic bm12 spleen cells (bm12-->CD4KO group) showed no evidence of cGVH disease. They made no detectable autoantibodies, including anti-chromatin, anti-dsDNA, anti-ssDNA, and rheumatoid factor. They survived at least 20 wks after induction of cGVH disease; and they did not develop nephritis, based on the absence of detectable levels of proteinuria and normal renal histology at the time of sacrifice. By contrast, CD8KO B6 mice (bm12-->CD8KO group) and normal B6 mice (bm12-->B6 group) injected with bm12 spleen cells generally showed similar levels of mortality, nephritis, and autoantibodies, although the autoantibody titers declined somewhat after week 8 in the bm12-->CD8KO group. Control groups of recipients injected with B6 spleen cells showed no induction of autoantibodies. A surprising finding, however, was that the B6-->CD8KO group developed severe histologic glomerulonephritis in the absence of autoantibodies and with decreased immune deposits. These results indicate that endogenous (host) CD4+ T cells play an essential role in the cGVH autoimmune syndrome.
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PMID:The role of host (endogenous) T cells in chronic graft-versus-host autoimmune disease. 983 67

To investigate the role of costimulation in autoimmune glomerulonephritis that develops in the setting of murine chronic graft-vs-host disease (cGVHD), we examined the effects of blocking CD40L, a costimulatory marker expressed on activated CD4+ T cells, in recipient mice. These studies addressed the potential role of CD40L blockade in preventing disease and in downregulating its expression in animals with evidence of autoreactivity. Animals treated acutely with anti-CD40L antibody at disease induction do not develop circulating anti-DNA antibodies, proteinuria, or histologic evidence of renal disease. If treatment is delayed for two weeks, after circulating anti-DNA antibodies are apparent, all animals develop massive proteinuria by 14 weeks after disease induction. Renal histology of kidneys from the delayed treatment and control groups reveal similar glomerular immune deposits, and intense staining for CD4, ICAM-1, and I-A(b) in areas of mononuclear cell infiltration. Long-term treatment studies begun two weeks after disease induction is not disease-protective, as all animals develop massive proteinuria and renal disease by 14 weeks. These studies suggest that early CD40L signaling events are critical to induction of allogeneic interactions and autoreactivity in cGVHD, but that short-term or chronic CD40L blockade, once autoreactivity is evident, does not abrogate systemic autoreactivity and renal involvement.
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PMID:Immune reactivity following CD40L blockade: role in autoimmune glomerulonephritis in susceptible recipients. 1043 91

There is no consensus regarding the specific management of HIV-associated nephrotic syndrome. We report a child whose first manifestation of human immunodeficiency virus type 1 (HIV-1) infection was nephropathy and wasting syndrome associated with profound immunodeficiency. The patient had a dramatic clinical and immunologic response to triple antiretroviral therapy delivered through a gastrostomy tube, with complete resolution of nephrotic syndrome. A 51/2-year-old African-American girl presented with a 2-week history of cough, chest pain, vomiting, loose stools, abdominal distention, anorexia, and fever. In addition, she had recurrent oral thrush. Her weight and height were below the 5th percentile. She was chronically ill, appearing with oropharyngeal thrush and pitting edema in lower extremities. She had scattered rhonchi and decreased breath sounds on both lung bases. Her abdomen was distended and diffusely tender. A chest radiograph showed consolidation of the right upper and left lower lobes with bilateral pleural effusion. Admission laboratories were consistent with nephrotic syndrome. Streptococcus pneumoniae grew from the blood culture and the child responded well to treatment with intravenous ceftriaxone. She was found to be HIV-infected, her CD4(+) cell count was 3 cells/mcL and her plasma HIV-1 RNA was >750 000 copies/mL. A percutaneous gastrostomy tube was placed for supplemental nutrition. She was treated with stavudine, lamivudine, and nelfinavir via gastrostomy tube with good clinical response. Twenty-one months after instituting antiretroviral therapy, her weight and height had increased to the 50th and 10th percentile respectively, and she had complete resolution of her nephrotic syndrome. Her CD4(+) cell count increased to 1116 cells/mcL and her viral load has remained undetectable. HIV-1 associated nephrotic syndrome has been described in children with profound immunodeficiency. The course of untreated HIV-associated nephrotic syndrome is rapid progression to renal failure in up to 40% of the children. Regardless of the presence of renal insufficiency, if untreated, it is uniformly fatal. A modest improvement of HIV-1 associated nephrotic syndrome has been observed in patients treated with zidovudine. Steroid and cyclosporine treatment have resulted in improved renal function but long-term use of immunosuppressive therapy has raised concerns about safety. We have described, to our knowledge, the first child with HIV-associated nephrotic syndrome who had a remarkable clinical, immunologic, and virologic response to triple-drug combination therapy given by gastrostomy tube, with complete resolution of proteinuria and normalization of the serum albumin. She also had a striking improvement in weight, height, and quality-of-life. Whether the presence of a gastrostomy tube contributed to the excellent response because of improved compliance is unknown, but warrants systematic evaluation.
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PMID:Resolution of HIV-associated nephrotic syndrome with highly active antiretroviral therapy delivered by gastrostomy tube. 1058 95

During the development of nephrotoxic nephritis (NTN) in the mouse, we find that a variety of chemokines and chemokine receptors are induced: CCR1 (RANTES, MIP-1alpha), CCR2 (MCP-1), CCR5 (RANTES, MIP-1alpha, MIP-1beta), CXCR2 (MIP-2), and CXCR3 (IP-10). Their timing of expression indicated that CXCR2 and CCR1 are probably important in the neutrophil-dependent heterologous phase of the disease, whereas CCR1, CCR2, CCR5, and CXCR3 accompany the subsequent mononuclear cell infiltration characteristic of autologous disease. We therefore assessed the role of CCR1 in NTN using CCR1(-/-) mice. We found that neutrophil accumulation in CCR1(-/-) mice was comparable to that in wild-type animals but that renal recruitment of CD4(+) and CD8(+) T cells and macrophages increased significantly. Moreover, CCR1(-/-) mice developed more severe glomerulonephritis than did controls, with greater proteinuria and blood urea nitrogen, as well as a higher frequency of crescent formation. In addition, CCR1(-/-) mice showed enhanced Th1 immune responses, including titers of antigen-specific IgG2a antibody, delayed-type hypersensitivity responses, and production of IFN-gamma and TNF-alpha. Lastly, using recombinant proteins and transfected cells that overexpressed CCR1, we demonstrated that MIP-1alpha, but not RANTES, bound CCR1 and induced cell chemotaxis. Thus, rather than simply promoting leukocyte recruitment during NTN, CCR1 expression profoundly alters the effector phase of glomerulonephritis. Therapeutic targeting of chemokine receptors may, on occasion, exacerbate underlying disease.
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PMID:Lack of chemokine receptor CCR1 enhances Th1 responses and glomerular injury during nephrotoxic nephritis. 1058 18


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