Human Urinary Proteome in Vesicoureteral Reflux
Ontology highlight
ABSTRACT:
INSTRUMENT(S): Q Exactive
ORGANISM(S): Homo Sapiens (human)
TISSUE(S): Urine
SUBMITTER: 
Patricia Cho
LAB HEAD: Richard S. Lee
PROVIDER: PXD010469 | Pride | 2018-10-05
REPOSITORIES: Pride
Publications
Characterizing Patients with Recurrent Urinary Tract Infections in Vesicoureteral Reflux: A Pilot Study of the Urinary Proteome.
Vitko Dijana D Cho Patricia S PS Kostel Stephen A SA DiMartino Shannon E SE Cabour Lily D LD Migliozzi Matthew A MA Logvinenko Tanya T Warren Peter G PG Froehlich John W JW Lee Richard S RS
Molecular & cellular proteomics : MCP 20200102 3
Recurrent urinary tract infections (UTIs) pose a significant burden on the health care system. Underlying mechanisms predisposing children to UTIs and associated changes in the urinary proteome are not well understood. We aimed to investigate the urinary proteome of a subset of children who have vesicoureteral reflux (VUR) and recurrent UTIs because of their risk of developing infection-related renal damage. Improving diagnostic modalities to identify UTI risk factors would significantly alter t ...[more]
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Project description:Renal scarring is a serious complication of chronic pyelonephritis due to vesicoureteral reflux, and requires specific biomarker for indication of early intervention. We investigated global expression profile of kidney during renal scarring formation using rat pyelonephritis model. An inoculum of the DS-17 strain Escherchia coli was injected directly into renal cortex of Wister rat. Histologically, renal scarring developed during 3 and 4 weeks after injection. The time course expression profile of approximately 20,500 genes was analyzed using high density oligonucleotide microarray followed by validation using real time RT-PCR. Most of up-regulated genes during this experimental renal scarring were associated with immune and defense response, including cytokines, chemokines, their receptors, complements, and adhesion molecules as well as proteins related to extra cellular matrix. These genes were up-regulated as early as 1 week after injection when histological examination did not show fibrotic change yet, peaked at 2 weeks and gradually decreased thereafter. However, a subset of cytokine genes is persistently activated even in 6 weeks after the injection, which are involved in TGF-β related tissue regeneration pathway or IL-1β related pathway. The products of these genes may potentially be the source of novel non-invasive diagnostic or prognostic biomarkers for renal scarring. Experiment Overall Design: Experimental pyelonephritis was produced by standard method of direct infection of rat kidney. In brief, animals were anesthetized with pentobarbital intraperitoneally. The kidneys were exposed through a midline abdominal incision. An inoculum of 1x109 colony-forming units / 0.1 ml of Escherchia coli was injected directly into bilateral renal cortex of Wister rat using 26-gauge needle. We used DS-17 or NU-14 strains, both of which has type 1 and P pili, and SEC strain, which has only type 1 pili. Control rats received isotonic saline instead of bacterial solution. Both test and control kidneys were harvested at 1, 2, 4 and 6 weeks after injection. The kidney samples (1x1x2 mm each) were obtained including the injection site, which was easily identified by surface color change. Then we cut the kidney into half; one was used for microscopic examination and the other half was immediately frozen in liquid nitrogen for later RNA extraction.
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Project description:Background. Chronic renal failure is characterized by progressive renal scarring and accelerated cardiovascular disease. In animal models, this is thought to be due to non-dialyzable uremic toxins M-bM-^@M-^S small, protein-bound molecules normally secreted via Organic Anion Transporters (OATs) in the proximal renal tubule,rather than filtered at the glomerulus. The best studied of these is indoxyl sulfate (IS). Methods. We examined global gene expression responses in cultured normal human renal tubular cells incubated with control plasma (n=5) or pre- and post-dialysis uremic plasma (n=10). Results. GeneSpring analysis of microarrays revealed significantly altered expression of 2016 genes. The expression of 537 genes M-bM-^@M-^\normalizedM-bM-^@M-^] in post-dialysis plasma, suggesting removal of M-bM-^@M-^\low molecular weight uremic toxinsM-bM-^@M-^] by dialysis. The expression of the majority of dysregulated genes (1479) was not normalized in post-dialysis plasma. These likely represent the effects of substances not effectively removed by dialysis (M-bM-^@M-^\protein-bound uremic toxinsM-bM-^@M-^]). Addition of indoxyl sulfateto control plasma simulated most effects (81.1%) of uremic plasma, while the addition of probenecid, an OAT inhibitor, to uremic plasma reversed most changes in gene expression. Analysis of molecular programs with the Gene Set Enrichment Analysis and the DAVID database revealed patterns common to indoxyl sulfate-treated control plasma, pre-dialysis, and post-dialysis uremic plasma. These included increased cell cycle, pro-inflammatory, and pro-fibrotic molecular programs, particularly genes in the TGF-M-NM-2 pathway. Conclusion: These findings provide insight into the role of non-dialyzable, protein-bound uremic toxins in the pathogenesis of renal scarring and uremic vasculopathy. The GSEA patterns confirm that inflammatory and fibrotic programs are active. Transcriptomic remodeling in response to external stimulus RNA from non-immortalized cultured renal cortical cells incubated with plasma samples from 5 controls, 10 uremics pre-dialysis, 10 uremics post-dialysis, 5 controls with indoxyl sulfate added, 5 uremics pre-dialysis with probenecid added, 5 uremics post-dialysis with indoxyl sulfate added
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