Effects of a Tricaprylin Emulsion on Anti-glomerular Basement Membrane Glomerulonephritis in Rats
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ABSTRACT:
ORGANISM(S): Rattus norvegicus
PROVIDER: GSE46295 | GEO | 2015/07/14
SECONDARY ACCESSION(S): PRJNA198646
REPOSITORIES: GEO
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Project description:Expression data from rat with anti-glomerular basement membrane nephritis (anti-GBM). We used microarrays to analyze the transcriptome of kidney from anti-GBM model rat with or without drug treatment RNA from whole kidneys was extracted and processed for hybridization on Affymetrix microarrays.
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Project description:We analyzed the impact of the genetic background during experimental passive non-accelerated anti-glomerular basement membrane glomerulonephritis (anti-GBM-GN) (an equivalent to nephrotoxic nephritis) in two different mouse genetic backgrounds (C57BL6/J vs 129S2svPAS/crl). Glomerular extracts have been made at an early time point (e.g day 4 of the induction of the glomerulonephritis). RNA have been extracted following standard procedures.
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Project description:The glomerular filtration barrier prevents large serum proteins from being lost into the urine. It is not known, however, why the filter does not routinely clog with large proteins that enter the glomerular basement membrane (GBM). Here we provide evidence that an active transport mechanism exists to remove immunoglobulins that accumulate at the filtration barrier. We found that FcRn, an IgG and albumin transport receptor, is expressed in podocytes and functions to internalize IgG from the GBM. Mice lacking FcRn accumulated IgG in the GBM as they aged and tracer studies showed delayed clearance of IgG from the kidneys of FcRn deficient mice. Supporting a role for this pathway in disease, saturating the clearance mechanism potentiated the pathogenicity of nephrotoxic sera. These studies support the idea that podocytes play an active role in removing proteins from the GBM and suggest that genetic or acquired impairment of the clearance machinery is likely to be a common mechanism promoting glomerular diseases. Keywords: Unique cell type expression analysis
2008-01-01 | GSE10017 | GEO
Project description:The glomerular filtration barrier prevents large serum proteins from being lost into the urine. It is not known, however, why the filter does not routinely clog with large proteins that enter the glomerular basement membrane (GBM). Here we provide evidence that an active transport mechanism exists to remove immunoglobulins that accumulate at the filtration barrier. We found that FcRn, an IgG and albumin transport receptor, is expressed in podocytes and functions to internalize IgG from the GBM. Mice lacking FcRn accumulated IgG in the GBM as they aged and tracer studies showed delayed clearance of IgG from the kidneys of FcRn deficient mice. Supporting a role for this pathway in disease, saturating the clearance mechanism potentiated the pathogenicity of nephrotoxic sera. These studies support the idea that podocytes play an active role in removing proteins from the GBM and suggest that genetic or acquired impairment of the clearance machinery is likely to be a common mechanism promoting glomerular diseases. Experiment Overall Design: Total RNA for genechip analysis was derived from two sources: Experiment Overall Design: 1) Primary mouse podocytes isolated by FACS sorting of collagenase digested glomeruli Experiment Overall Design: 2) In vitro differentiated conditionally immortalized mouse podocyte cell line. Experiment Overall Design: After obtaining genechip data, the expression of various IgG and albumin receptors was queried in the genechip data and then confirmed by RT-PCR.
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Project description:We investigated a glomerulonephritis (GN) model in rats induced by nephrotoxic serum (NTS) which contains antibodies against the glomerular basement membrane (GBM). The anti-GBM GN model in rats is widely used since its biochemical and histopathological characteristics are similar to crescentic nephritis and Goodpasture's disease in humans. Male Wistar Kyoto (WKY) and Sprague Dawley (SD) rats were dosed once with 1, 2.5 and 5 ml/kg nephrotoxic serum (NTS) or 1.5 and 5 ml/kg NTS, respectively. GN and tubular damage were observed histopathologically in all treated rats after 14 days. To obtain insight into molecular processes during GN pathogenesis, mRNA expression was investigated in WKY and SD kidneys. The immunopathological processes during GN are still not fully understood and likely involve both innate and adaptive immunity. In the present study, several hundred mRNAs were found deregulated, which functionally were mostly associated with inflammation and regeneration. The ?-chain of the major histocompatibility complex class II RT1.B (Rt1-Bb) and complement component 6 (C6) were identified as two mRNAs differentially expressed between WKY and SD rat strains which could be related to known different susceptibilities to NTS of different rat strains; both were increased in WKY and decreased in SD rats. Increased Rt1-Bb expression in WKY rats could indicate a stronger and more persistent cellular reaction of the adaptive immune system in this strain, in line with findings indicating adaptive immune reactions during GN. The complement cascade is also known to be essential for GN development, especially terminal cascade products like C6. Two different rat strains (WKY and SD) were dosed with different doses of NTS and after 14 days rats were euthanized and kidneys were removed for RNA extraction and hybridization on Affymetrix microarrays. We sought to analyze the deregulation of gene expression during NTS-induced glomerulonephritis and to compare the effect in the two rat strains.
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Project description:We isolated the extracellular matrix from human podocytes and endothelial cells in monoculture and coculture and analysed the matrix proteins by mass-spectrometry. The glomerular basement membrane (GBM) is a specialized extracellular matrix (ECM) compartment within the glomerulus and is known to contain tissue-restricted isoforms of collagen IV and laminin. It is integral to the capillary wall and therefore functionally linked to glomerular filtration. While the composition of the GBM has been investigated with global and candidate-based approaches, the relative contributions of glomerular cell types to the production of ECM is not well understood. To enable the characterization of specific cellular contributions to the GBM, we analyzed ECM isolated from podocytes and glomerular endothelial cells in vitro using mass spectrometrybased proteomics. These analyses identified cell typespecific differences in ECM composition, indicating distinct contributions to glomerular ECM assembly. Coculture of podocytes and endothelial cells resulted in an altered composition and organization of ECM compared to monoculture ECMs from single cell types, suggesting a role for cell-cell crosstalk in the production of glomerular ECM. This was supported by the identification of basement membranelike ECM deposition between cocultured cells using electron microscopy. Importantly, compared to monoculture, the coculture ECM proteome better resembled a tissue-derived glomerular ECM dataset, indicating its relevance to GBM in vivo. Protein network analyses revealed a common core of 35 highly connected structural ECM proteins that may be important for glomerular ECM assembly. Overall, these findings demonstrate the complexity of the glomerular ECM and suggest that both ECM composition and organization are context dependent. MS data analysis: Tandem mass spectra were extracted using extract_msn (Thermo Fisher Scientific) executed in Mascot Daemon (version 2.2.2; Matrix Science, London, UK). Peak list files were searched against a modified version of the IPI Human database (version 3.70; release date, 4 March 2010), containing ten additional contaminant and reagent sequences of non-human origin, using Mascot (version 2.2.03; Matrix Science).2 Carbamidomethylation of cysteine was set as a fixed modification; oxidation of methionine and hydroxylation of proline and lysine were allowed as variable modifications. Only tryptic peptides were considered, with up to one missed cleavage permitted. Monoisotopic precursor mass values were used, and only doubly and triply charged precursor ions were considered. Mass tolerances for precursor and fragment ions were 0.4 Da and 0.5 Da, respectively. MS datasets were validated using rigorous statistical algorithms at both the peptide and protein level3 4 implemented in Scaffold (version 3.00.06; Proteome Software, Portland, OR, USA). Protein identifications were accepted upon assignment of at least two unique validated peptides with „90% probability, resulting in „99% probability at the protein level. These acceptance criteria resulted in an estimated protein false discovery rate of 0.1% for all datasets.
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