PubMed Health⌕ Search

Biomedical subjects

Peter Doran

Publications and source records attributed to Peter Doran.

9 recordsLinked to original sources
PubMed2005

Expression of gremlin, a bone morphogenetic protein antagonist, in human diabetic nephropathy.

BACKGROUND: We report the induction of gremlin, a bone morphogenetic protein antagonist, in cultured human mesangial cells exposed to high glucose and transforming growth factor beta (TGF-beta) levels in vitro and kidneys from diabetic rats in vivo. METHODS: Gremlin expression was assessed in human diabetic nephropathy by means of in situ hybridization, immunohistochemistry, and real-time polymerase chain reaction and correlated with clinical and pathological indices of disease. RESULTS: Gremlin was not expressed in normal human adult kidneys. Conversely, abundant gremlin expression was observed in human diabetic nephropathy. Although some gremlin expression was observed in occasional glomeruli, gremlin expression was most prominent in areas of tubulointerstitial fibrosis, where it colocalized with TGF-beta expression. Gremlin messenger RNA levels correlated directly with renal dysfunction, determined by means of serum creatinine level, but not with proteinuria level. There was a strong correlation between gremlin expression and tubulointerstitial fibrosis score. CONCLUSION: In aggregate, these results indicate that the developmental gene gremlin reemerges in the context of tubulointerstitial fibrosis in diabetic nephropathy and suggests a role for TFG-beta as an inducer of gremlin expression in this context.

Bone Morphogenetic Proteins↗
PubMed2005

Microarray and bioinformatic detection of novel and established genes expressed in experimental anti-Thy1 nephritis.

BACKGROUND: Microarray technology is a powerful tool that can probe the molecular pathogenesis of renal injury. In this present study microarray analysis was used to monitor serial changes in the renal transcriptome of a rat model of mesangial proliferative glomerulonephritis. Administration of anti-Thy1 antibody results in phases of acute mesangial injury (day 2), cell proliferation (day 5), matrix expansion (days 5 and 7), and subsequent healing (day 14). METHODS: Using Affymetrix (RAE230A) microarrays coupled with sequential primary biologic function-focused and secondary "baited" global cluster analysis, a cohort of established and putative novel modulators of mesangial cell turnover was identified. RESULTS: Cluster analysis of proliferative genes identified a number of gene expression profiles. The most striking pattern was increased gene expression at day 5, a cluster that included platelet-derived growth factor (PDGF), cyclins and transforming growth factor-beta (TGF-beta). The gene expression patterns identified by primary focused cluster analysis were used as bioinformatic bait and resulted in the identification of novel families of genes such as the S100 family. The expression of established and novel genes was confirmed using reverse transcription-polymerase chain reaction (RT-PCR). Next, in vivo gene expression was compared to PDGF-stimulated mesangial cells in vitro revealing similar patterns of dysregulation. CONCLUSION: Transcriptomic analysis defined both known and novel molecules involved in mesangial cell proliferation in vitro and in vivo and defined a panel of molecules that are potential contributors to mesangial cell dysfunction in glomerular disease.

Animals↗
PubMed2004

Sequential extracellular matrix-focused and baited-global cluster analysis of serial transcriptomic profiles identifies candidate modulators of renal tubulointerstitial fibrosis in murine adriamycin-induced nephropathy.

Transcriptome analysis using microarray technology represents a powerful unbiased approach for delineating pathogenic mechanisms in disease. Here molecular mechanisms of renal tubulointerstitial fibrosis (TIF) were probed by monitoring changes in the renal transcriptome in a glomerular disease-dependent model of TIF (adriamycin nephropathy) using Affymetrix (mu74av2) microarray coupled with sequential primary biological function-focused and secondary "baited"-global cluster analysis of gene expression profiles. Primary cluster analysis focused on mRNAs encoding matrix proteins and modulators of matrix turnover as classified by Onto-Compare and Gene Ontology and identified both molecules and pathways already implicated in the pathogenesis of TIF (e.g. transforming growth factor beta1-CTGF-fibronectin-1 pathway) and novel TIF-associated genes (e.g. SPARC and Matrilin-2). Specific gene expression patterns identified by primary extracellular matrix-focused cluster analysis were then used as bioinformatic bait in secondary global clustering, with which to search the renal transcriptome for novel modulators of TIF. Among the genes clustering with ECM proteins in the latter analysis were endoglin, clusterin, and gelsolin. In several notable cases (e.g. claudin-1 and meprin-1beta) the pattern of gene expression identified in adriamycin nephropathy in vivo was replicated during transdifferentiation of renal tubule epithelial cells to a fibroblast-like phenotype in vitro on exposure to transforming growth factor-beta and epidermal growth factor suggesting a role in fibrogenesis. The further exploration of these complex gene networks should shed light on the core molecular pathways that underpin TIF in renal disease.

Animals↗
PubMed2004

Gene expression fingerprints in human tubulointerstitial inflammation and fibrosis as prognostic markers of disease progression.

BACKGROUND: Gene expression profiling of nephropathies may facilitate development of diagnostic strategies for complex renal diseases as well as provide insight into the molecular pathogenesis of kidney diseases. To test molecular based renal disease categorization, differential gene expression profiles were compared between control and hydronephrotic kidneys showing varying degrees of inflammation and fibrosis. METHODS: RNA expression profiles from 9 hydronephrotic and 3 control kidneys were analyzed using small macroarrays dedicated to genes involved in cell-cell contact, matrix turnover, and inflammation. In parallel, the degree of tubulointerstitial inflammation, fibrosis, and tubular atrophy using light microscopy and quantitative immunohistochemical parameters was determined. RESULTS: Hierarchic clustering and self-organizing maps led to a gene expression dendrogram with three distinct nodes representing the control group, four kidneys with high inflammation, and five kidneys giving high fibrosis scores. To evaluate the clinical applicability of the marker set, the expression of nine genes (6Ckine, IL-8, MMP-9, MMP-3, MMP-7, urokinase R, CXCR5, integrin-beta4, and pleiotrophin) was tested in tubulointerstitial samples from routine renal biopsies. Seven mRNA markers showed differential regulation in inflammation and fibrosis in the biopsy population. Clinical follow-up revealed stringent correlation between gene expression data and progression of renal disease, and allowed segregation of the biopsies into progressive or stable disease course based on gene expression profiles. CONCLUSION: This study suggests the feasibility of gene expression-based disease categorization in human nephropathies based on the extraction of marker gene sets.

Adult↗
PubMed2003

Transcriptome profiling and the pathogenesis of diabetic complications.

Diabetes is an escalating problem worldwide and a major cause of vascular disease, renal failure, and blindness, among other complications. The cellular mediators of high glucose-induced injury include activation of protein kinase C, accumulation of cell sorbitol from increased flux through the aldose reductase pathway, and generation of advanced glycosylation end products and reactive oxygen species, among others. Current strategies for preventing and slowing the progression of the macrovascular and microvascular complications of diabetes include optimization of glycemic control and BP, angiotensin-converting enzyme inhibitors and angiotensin II blockers, and HMG CoA reductase inhibitors. However, there is an urgent need to develop new therapeutic strategies, as these interventions, although they may slow, rarely halt the progression of diabetic complications. Central to this process is the elucidation of the molecular events that drive this complex disease and that are potential therapeutic targets. This review discusses the promise offered in this regard by global monitoring of cellular or tissue mRNA expression (so-called transcriptomics) and illustrates the potential of this approach by focusing on recent studies on the pathogenesis of diabetic nephropathy.

Actins↗
PubMed2002

15-Epi-16-(para-fluorophenoxy)-lipoxin A(4)-methyl ester, a synthetic analogue of 15-epi-lipoxin A(4), is protective in experimental ischemic acute renal failure.

Lipoxins are endogenous lipoxygenase-derived eicosanoids, generated during inflammatory, hypersensitivity, and vascular events, that display vasodilatory, antiinflammatory, and pro-resolution activity. Here, we evaluated the efficacy of 15-epi-16-(para-fluorophenoxy)-lipoxin A(4)-methyl ester (15-epi-16-(FPhO)-LXA(4)-Me), a stable synthetic analogue of aspirin-triggered 15-epi-lipoxin A(4) in ischemic acute renal failure (ARF) in NIH Swiss mice. ARF was induced by 30-min crossclamping of renal pedicles and was associated with elevated serum creatinine, morphologic injury, polymorphonuclear leukocyte (PMN) recruitment, and increased mRNA levels for adhesion molecules (intercellular adhesion molecule-1 [ICAM-1] and vascular cell adhesion molecule-1 [VCAM-1]), chemokines (growth regulated oncogene-1 [GRO1]), and cytokines (interleukin-1beta [IL-1beta] and IL-6) after 24-h reperfusion. A single bolus of 15-epi-16-(FPhO)-LXA(4)-Me afforded striking functional (mean +/- SEM creatinine in mg/dl: sham-operated, 0.77 +/- 0.04; ARF + vehicle, 2.49 +/- 0.19; ARF + 15-epi-16-(FPhO)-LXA(4)-Me, 0.75 +/- 0.12; P < 0.001) and morphologic protection and reduced PMN infiltration. Treatment with 15-epi-16-(FPhO)-LXA(4)-Me was also associated with lower IL-1beta, IL-6, and GRO1 mRNA levels, whereas ICAM-1 and VCAM-1 mRNA levels were unchanged. Compatible with these results, LXA(4) blunted chemoattractant-stimulated PMN migration across HK-2 renal epithelial cell monolayers in vitro, but it did not inhibit cytokine-induced HK-2 ICAM-1 expression or adhesiveness for PMN. Interestingly 15-epi-16-(FPhO)-LXA(4)-Me-treated animals also displayed increased renal mRNA levels for suppressors of cytokine signaling-1 (SOCS-1) and SOCS-2, but not CIS-1, endogenous inhibitors of cytokine-elicited Jak/Stat-signaling pathways. These results indicate that 15-epi-16-(FPhO)-LXA(4)-Me is protective in renal ischemia reperfusion injury in vivo, at least partially by modulating cytokine and chemokine expression and PMN recruitment, and provides a rationale for further exploration of the efficacy of LXA(4) structural analogues in ischemic ARF and other renal diseases.

Acute Kidney Injury↗
PubMed2002

Repuncturing the renal biopsy: strategies for molecular diagnosis in nephrology.

As has been exemplified by recent progress in the classification of cancer, future approaches to enhance the clinical diagnostic power of tissue biopsies may be based on gene expression profiles. A series of strategies to translate these approaches to the diagnosis of renal disease is here proposed. The theoretical and technical problems resulting from the small amount of starting material available from renal biopsies will be specifically addressed. A preliminary study with cDNA array-based expression data obtained from kidneys with tubulointerstitial inflammation and fibrosis suggests the feasibility of distinguishing molecular categories of renal disease. Finally, a combined conventional and molecular work-up of renal biopsies will be suggested. These approaches should add a new dimension to biopsy interpretation and provide novel information concerning renal pathogenesis, diagnosis, prognosis, and differential therapy. A coordinated effort from nephrologists and pathologists in large multicenter trials will be required to achieve this goal. It is hoped that this outlook will lead to stimulating discussions and the implementation of these innovative ideas in nephrology.

Biopsy↗
PubMed2002

Gene responses to hyperglycaemia.

The rising tide of diabetic nephropathy (DN) is arguably the most challenging clinical problem confronting nephrologists at the beginning of the new century. Central to the development of novel diagnostic and therapeutic strategies will be the elucidation of the molecular events that drive this complex disease. In this review, we briefly discuss the major growth factors and cytokines identified as mediators of tissue injury in DN in the "pre-gene subtraction" era. We then highlight the remarkable array of new molecular players already identified with the introduction of gene subtraction techniques, such as differential-display PCR, suppression-subtractive hybridization, and nucleotide micro-arrays, and discuss the likely impact of these technologies going forward. Finally, we summarize the current knowledge on the cell signalling events triggered by high glucose levels that influence gene expression in DN and that represent additional therapeutic targets in this setting.

Diabetic Nephropathies↗