| 1. |
- Herrera, Marcela, et al.
(författare)
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Inhibition of T-cell activation by CTLA4-Fc is sufficient to ameliorate proteinuric kidney disease.
- 2017
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Ingår i: American journal of physiology. Renal physiology. - : American Physiological Society. - 1522-1466 .- 1931-857X. ; 312:4
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Tidskriftsartikel (refereegranskat)abstract
- Diabetic Nephropathy (DN) remains an unmet medical challenge as its prevalence is projected to continue to increase and specific medicines for treatment remain undeveloped. Activation of the immune system, in particular T-cells, is emerging as a possible mechanism underlying DN disease progression in humans and animal models. We hypothesized that inhibition of T-cell activation will ameliorate DN. Interaction of B7-1 (CD80) on the surface of antigen presenting cells with its binding partners, CTLA4 (CD152) and CD28 on T-cells, is essential for T-cell activation. In this study we used the soluble CTLA4-Fc fusion protein Abatacept to block cell surface B7-1, preventing the cellular interaction and inhibiting T-cell activation. When Abatacept was dosed in an animal model of diabetes-induced albuminuria, it reduced albuminuria in both prevention and intervention modes. The number of T-cells infiltrating the kidneys of DN animals correlated with the degree of albuminuria and treatment with Abatacept reduced the number of renal T-cells. As B7-1 induction has been recently proposed to underlie podocyte damage in DN, Abatacept could be efficacious in DN by protecting podocytes. However, this does not appear to be the case as B7-1 was not expressed in: 1) kidneys of DN animals; 2) stimulated human podocytes in culture; or 3) glomeruli of DN patients. We conclude that Abatacept ameliorates DN by blocking systemic T-cell activation and not by interacting with podocytes.
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| 2. |
- Valastro, Barbara, et al.
(författare)
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Expression pattern of JunD after acute or chronic l-DOPA treatment: Comparison with DeltaFosB.
- 2007
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Ingår i: Neuroscience. - : Elsevier BV. - 1873-7544 .- 0306-4522. ; 144:Oct 19, s. 198-207
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Tidskriftsartikel (refereegranskat)abstract
- In this study, we have used 6-hydroxydopamine-lesioned rats to examine changes in striatal junD and fosB/Delta fosB expression induced by acute and chronic treatment with (L)-DOPA (5 and 15 days). Changes at the protein levels were studied using Western immunoblotting while mRNA changes were compared using in situ hybridization histochemistry. We observed a significant increase in the level of Delta FosB proteins after chronic treatment with L-DOPA, an effect that was not observed for JunD proteins. In addition, the upregulation of Delta FosB was already present after an acute treatment but increased upon chronic treatment. By contrast, junD and Delta fosB mRNA were both upregulated significantly above control levels after an acute injection of L-DOPA. In conclusion, this study suggests a differential expression pattern of junD and Delta fosB in a rat model of L-DOPA-induced dyskinesia. The upregulation of Delta FosB protein, but not JunD, is likely to reflect an increased stability of the Delta FosB proteins without ongoing enhanced transcription of the encoding genes. (c) 2006 IBRO. Published by Elsevier Ltd. All rights reserved.
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| 3. |
- Valastro, Barbara, et al.
(författare)
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Proteomic analysis of striatal proteins in the rat model of l-DOPA-induced dyskinesia.
- 2007
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Ingår i: Journal of Neurochemistry. - : Wiley. - 1471-4159 .- 0022-3042. ; 102:4, s. 1395-1409
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Tidskriftsartikel (refereegranskat)abstract
- L-DOPA-induced dyskinesia (LID) is among the motor complications that arise in Parkinson's disease (PD) patients after a prolonged treatment with L-DOPA. To this day, transcriptome analysis has been performed in a rat model of LID [Neurobiol. Dis., 17 (2004), 219] but information regarding the proteome is still lacking. In the present study, we investigated the changes occurring at the protein level in striatal samples obtained from the unilaterally 6-hydroxydopamine-lesion rat model of PD treated with saline, L-DOPA or bromocriptine using two-dimensional difference gel electrophoresis and mass spectrometry (MS). Rats treated with L-DOPA were allocated to two groups based on the presence or absence of LID. Among the 2000 spots compared for statistical difference, 67 spots were significantly changed in abundance and identified using matrix-assisted laser desorption/ionization time-of-flight MS, atmospheric pressure matrix-assisted laser desorption/ionization and HPLC coupled tandem MS (LC/MS/ MS). Out of these 67 proteins, LID significantly changed the expression level of five proteins: alpha beta-crystalin, gamma-enolase, guanicloacetate methyltransferase, vinculin, and proteasome alpha-2 subunit. Complementary techniques such as western immunoblotting and immunohistochernistry were performed to investigate the validity of the data obtained using the proteomic approach. In conclusion, this study provides new insights into the protein changes occurring in LID.
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