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      Glomerulonefritis focal y segmentaria en paciente con sarcoidosis pulmonar Translated title: Focal segmental glomerulonephritis in patients with pulmonary sarcoidosis

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          The spectrum of focal segmental glomerulosclerosis: new insights.

          Focal segmental glomerulosclerosis (FSGS) is a disease with diverse histologic patterns and etiologic associations. Genetic, toxic, infectious and inflammatory mediators have been identified. This review will focus on new evidence supporting the potential mechanistic basis underlying the histologic variants and their clinical relevance. Evidence from animal models and in-vitro studies suggests that injury inherent within or directed to the podocyte is a central pathogenetic factor. Disruption of signaling from any of the podocyte's specialized membrane domains, including slit diaphragm, apical and basal membranes, or originating at the level of the actin cytoskeleton, may promote the characteristic response of foot process effacement. Irreversible podocyte stress leading to podocyte depletion through apoptosis or detachment is a critical mechanism in most forms of FSGS. In the collapsing variant, podocyte dysregulation leads to podocyte dedifferentiation and glomerular epithelial cell proliferation. Translation studies in humans and new evidence from animal models have provided mechanistic insights into the diverse phenotypes of FSGS.
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            Role of CD4+ T cells in sarcoidosis.

            Activated pulmonary CD4(+) T lymphocytes of the Th-1 type are essential for the inflammatory process in sarcoidosis, and IFN-gamma production is crucial for the characteristic granuloma formation. Both the T cells and their inflammatory mediators may constitute possible targets for immunotherapy. A particular T-cell subset, the T-cell receptor (TCR) AV2S3(+) bronchoalveolar lavage (BAL) CD4(+) T cells, is found at dramatically increased levels in the BAL fluid of human leukocyte antigen (HLA)-DRB1*0301-positive and/or HLA-DRB3*0101-positive patients with sarcoidosis. The AV2S3(+) BAL CD4(+) T cells strongly associate with the sarcoid inflammation, and future studies on this particular T-cell subset to reveal their specificity may lead to the identification of sarcoidosis-specific antigen(s). T-cell subpopulations with regulatory functions (i.e., natural killer T cells and T regulatory cells) have recently been described as abnormal in sarcoidosis. Dysfunctional regulatory T cells may allow T effector cells to contribute to the formation of granulomas, and they may thus be relevant for the inflammatory process in this disease. These findings are exciting news and will be of help in designing new treatment strategies.
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              Invariant Natural Killer T Cell Agonist Modulates Experimental Focal and Segmental Glomerulosclerosis

              A growing body of evidence demonstrates a correlation between Th2 cytokines and the development of focal and segmental glomerulosclerosis (FSGS). Therefore, we hypothesized that GSL-1, a monoglycosylceramide from Sphingomonas ssp. with pro-Th1 activity on invariant Natural Killer T (iNKT) lymphocytes, could counterbalance the Th2 profile and modulate glomerulosclerosis. Using an adriamycin(ADM)-based model of FSGS, we found that BALB/c mice presented albuminuria and glomerular degeneration in association with a Th2-like pro-fibrogenic profile; these mice also expressed a combination of inflammatory cytokines, such as IL-4, IL-1α, IL-1β, IL-17, TNF-α, and chemokines, such as RANTES and eotaxin. In addition, we observed a decrease in the mRNA levels of GD3 synthase, the enzyme responsible for GD3 metabolism, a glycolipid associated with podocyte physiology. GSL-1 treatment inhibited ADM-induced renal dysfunction and preserved kidney architecture, a phenomenon associated with the induction of a Th1-like response, increased levels of GD3 synthase transcripts and inhibition of pro-fibrotic transcripts and inflammatory cytokines. TGF-β analysis revealed increased levels of circulating protein and tissue transcripts in both ADM- and GSL-1-treated mice, suggesting that TGF-β could be associated with both FSGS pathology and iNKT-mediated immunosuppression; therefore, we analyzed the kidney expression of phosphorylated SMAD2/3 and SMAD7 proteins, molecules associated with the deleterious and protective effects of TGF-β, respectively. We found high levels of phosphoSMAD2/3 in ADM mice in contrast to the GSL-1 treated group in which SMAD7 expression increased. These data suggest that GSL-1 treatment modulates the downstream signaling of TGF-β through a renoprotective pathway. Finally, GSL-1 treatment at day 4, a period when proteinuria was already established, was still able to improve renal function, preserve renal structure and inhibit fibrogenic transcripts. In conclusion, our work demonstrates that the iNKT agonist GSL-1 modulates the pathogenesis of ADM-induced glomerulosclerosis and may provide an alternative approach to disease management.
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                Author and article information

                Contributors
                Role: ND
                Role: ND
                Role: ND
                Role: ND
                Role: ND
                Journal
                nefrologia
                Nefrología (Madrid)
                Nefrología (Madr.)
                Sociedad Española de Nefrología (Cantabria, Santander, Spain )
                0211-6995
                1989-2284
                2013
                : 33
                : 3
                : 431-433
                Affiliations
                [01] Aranjuez orgnameHospital del Tajo orgdiv1Unidad de Nefrología
                [02] Madrid orgnameHospital Universitario 12 de Octubre orgdiv1Servicio de Anatomía Patológica
                Article
                S0211-69952013000400025
                10.3265/Nefrologia.pre2012.Sep.11753
                23712235
                0cdb88d9-4957-493b-886d-6fd037ee8332

                This work is licensed under a Creative Commons Attribution-NonCommercial 3.0 International License.

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                Figures: 0, Tables: 0, Equations: 0, References: 13, Pages: 3
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                SciELO Spain


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