Altered expression of immune modulator and structural genes in neonatal unilateral ureteral obstruction

Silverstein, Douglas M.; Travis, Brett; Thornhill, Barbara A.; Schurr, Jill S.; Kolls, Jay; Leung, Jocelyn C.; Chevalier, Robert L.

doi:10.1046/j.1523-1755.2003.00067.x

Cited by 62 publications

(39 citation statements)

References 49 publications

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“…These include two-kidney, one-clip hypertension, 35 cyclosporin nephropathy, 36 renal ablation, 37 and unilateral ureteral obstruction. 38 Interestingly, although renal cortical eNOS mRNA is increased in children with ureteropelvic junction obstruction, enzyme activity is reduced in proportion to the severity of interstitial fibrosis and the reduction in creatinine clearance. 39 Also of note, eNOS gene polymorphisms are associated with reduced enzyme activity and the development of end-stage renal failure.…”

Section: Discussionmentioning

confidence: 99%

Lack of Endothelial Nitric-Oxide Synthase Leads to Progressive Focal Renal Injury

Forbes

Thornhill

Park

et al. 2007

The American Journal of Pathology

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Because endothelial nitric-oxide synthase (eNOS) is generally considered protective against renal injury , we examined eNOS knockout mice for kidney pathology. In 80% of the adults examined , the renal surface was marked by distinct indented scars containing crowded small glomeruli but lacking attached tubules. Although vasculature was intact in the scars , Bowman's space was dilated and glomerular tufts were degenerated. The atubular glomeruli were embedded in a dense interstitial matrix composed of cells positive for fibroblast (FSP-1) or macrophage (F4/80) markers , degenerated proximal tubules and collecting ducts , and diffuse fibrotic deposits. Surrounding regions of kidney contained mostly normal-appearing tubules , but enlarged or sclerotic glomeruli were also present. In neonatal animals , apoptosis and necrosis were concentrated in tubules within focal parenchymal zones , with narrowing of the glomerulotubular "neck." In summary , targeted deletion of eNOS in mice leads to progressive focal renal abnormalities , including glomerular hypoplasia , and tubular cell death , leading to separation of glomeruli from tubules and tubular disruption. These abnormalities begin developing during the normal up-regulation of eNOS in the maturing kidney and are similar to those of a variety of chronic renal disorders. Endogenous renal eNOS production therefore seems critical for the maintenance of nephron maturation and integrity. Endothelial nitric-oxide synthase (eNOS) is implicated in numerous aspects of renal vascular control and function. It is thought to exert a vasculoprotective effect by modulation of kidney blood flow through counterbalancing the effects of the renin-angiotensin system.1 Following NOS inhibition, the activity of the renin-angiotensin system is increased, with increased expression of fibronectin and ␣-smooth muscle actin. 2 Either angiotensin-converting enzyme inhibitors or angiotensin receptor antagonists ameliorate the consequent renal injury.2 In contrast, ischemic preconditioning increases renal eNOS protein expression and suppresses ischemic injury.3 As its name implies, eNOS is located within the renal vascular endothelium in the adult. However, recent findings indicate that, in neonatal rats, this enzyme is also transiently present in proximal tubules, 4 whereas eNOS mRNA is present in the inner medullary collecting duct in the adult.

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Section: Discussionmentioning

confidence: 99%

Lack of Endothelial Nitric-Oxide Synthase Leads to Progressive Focal Renal Injury

Forbes

Thornhill

Park

et al. 2007

The American Journal of Pathology

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“…39 In addition, lumican (as well as other proteoglycans) has been reported to be up-regulated in kidneys of rats experiencing unilateral ureteral obstruction. 41 These studies suggest that increased thickening of the ECM and possibly glomerulosclerosis may be accompanied by up-regulation of select proteoglycans, including lumican. Because the samples involved in the DASP study are from recently diagnosed patients, it is difficult to estimate the degree to which plasma hyperglycemia affects the morphology and function of the kidney.…”

Section: Lumicanmentioning

confidence: 99%

Application of Proteomics in the Discovery of Candidate Protein Biomarkers in a Diabetes Autoantibody Standardization Program Sample Subset

et al. 2007

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Novel biomarkers of type 1 diabetes must be identified and validated in initial, exploratory studies before they can be assessed in proficiency evaluations. Currently, untargeted "-omics" approaches are under-utilized in profiling studies of clinical samples. This report describes the evaluation of capillary liquid chromatography (LC) coupled with mass spectrometry (MS) in a pilot proteomic analysis of human plasma and serum from a subset of control and type 1 diabetic individuals enrolled in the Diabetes Autoantibody Standardization Program with the goal of identifying candidate biomarkers of type 1 diabetes. Initial high-resolution capillary LC-MS/MS experiments were performed to augment an existing plasma peptide database, while subsequent LC-FTICR studies identified quantitative differences in the abundance of plasma proteins. Analysis of LC-FTICR proteomic data identified five candidate protein biomarkers of type 1 diabetes. Alpha-2-glycoprotein 1 (zinc), corticosteroid-binding globulin, and lumican were 2-fold up-regulated in type 1 diabetic samples relative to control samples, whereas clusterin and serotransferrin were 2-fold up-regulated in control samples relative to type 1 diabetic samples. Observed perturbations in the levels of all five proteins are consistent with the metabolic aberrations found in type 1 diabetes. While the discovery of these candidate protein biomarkers of type 1 diabetes is encouraging, follow up studies are required for validation in a larger population of individuals and for determination of laboratory-defined sensitivity and specificity values using blinded samples.

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“…16 Significant upregulation of lumican is detected in renal sections of chronic neonatal UUO. 71 There is no direct evidence of lumican regulating apoptosis and infiltration in the kidney. However, taking into account its role in inducing apoptosis in tumor cells 72 and mouse embryonic fibroblasts 73 plus its ability to regulate macro-phage and neutrophil infiltration in the eye, 74 -76 one might speculate that enhanced expression of lumican may be involved in apoptosis and interstitial infiltration in the UUO model.…”

Section: Lumican and Fibromodulinmentioning

confidence: 99%

Small Leucine-Rich Proteoglycans in Kidney Disease

Schaefer¹

2011

Journal of the American Society of Nephrology

103

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Altered expression of immune modulator and structural genes in neonatal unilateral ureteral obstruction

Abstract: Multiple genes are aberrantly expressed in the kidney of rats subjected to chronic neonatal UUO. Elucidation of these genes involved in neonatal UUO may lead to new insight about congenital obstructive nephropathy.

Cited by 62 publications

References 49 publications

Lack of Endothelial Nitric-Oxide Synthase Leads to Progressive Focal Renal Injury

Lack of Endothelial Nitric-Oxide Synthase Leads to Progressive Focal Renal Injury

Application of Proteomics in the Discovery of Candidate Protein Biomarkers in a Diabetes Autoantibody Standardization Program Sample Subset

Small Leucine-Rich Proteoglycans in Kidney Disease

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