Comparative promoter analysis allows
            <i>de novo</i>
            identification of specialized cell junction-associated proteins

Cohen, Clemens D.; Klingenhoff, Andreas; Boucherot, Anissa; Nitsche, Almut; Henger, Anna; Brunner, Bodo; Schmid, Holger; Merkle, Monika; Saleem, Moin A.; Koller, Klaus Peter; Werner, Thomas; Gröne, Hermann Josef; Nelson, Peter J.; Kretzler, Matthias

doi:10.1073/pnas.0511257103

Cited by 113 publications

(114 citation statements)

References 41 publications

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“…Total RNA was isolated from microdissected glomeruli, reverse-transcribed, and linearly amplified according to a protocol reported previously. 23 Fragmentation, hybridization, staining, and imaging were performed according to the Affymetrix Expression Analysis Technical Manual for HG-U133A. Before microarray analysis Robust Multichip Average was applied.…”

Section: Rna Isolation Preparation and Microarray Experimentsmentioning

confidence: 99%

Human Nephrosclerosis Triggers a Hypoxia-Related Glomerulopathy

Neusser

Lindenmeyer

Moll

et al. 2010

The American Journal of Pathology

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In the kidney, hypoxia contributes to tubulointerstitial fibrosis, but little is known about its implications for glomerular damage and glomerulosclerosis. Chronic hypoxia was hypothesized to be involved in nephrosclerosis (NSC) or "hypertensive nephropathy." In the present study genome-wide expression data from microdissected glomeruli were studied to examine the role of hypoxia in glomerulosclerosis of human NSC. Functional annotation analysis revealed prominent regulation of hypoxia-associated biological processes in NSC, including angiogenesis, fibrosis, and inflammation. Glomerular expression levels of a majority of genes regulated by the hypoxia-inducible factors (HIFs) were significantly altered in NSC. Among these HIF targets, chemokine C-X-C motif receptor 4 (CXCR4) was prominently induced. Glomerular CXCR4 mRNA induction was confirmed by quantitative RT-PCR in an independent cohort with NSC but not in those with other glomerulopathies. By immunohistological analysis, CXCR4 showed enhanced positivity in podocytes in NSC biopsy specimens. This CXCR4 positivity was associated with nuclear localization of HIF1␣ only in podocytes of NSC, indicating transcriptional activity of HIF. As the CXCR4 ligand CXCL12/SDF-1 is constitutively expressed in podocytes, autocrine signaling may contribute to NSC. In addition, a blocking CXCR4 antibody caused significant inhibition of wound closure by podocytes in an in vitro scratch assay. These data support a role for CXCR4/CXCL12 in human NSC and indicate that hypoxia not only is involved in tubulointerstitial fibrosis but also contributes to glomerular damage in NSC. Hypoxia is considered a pivotal factor contributing to tubular atrophy and interstitial fibrosis, which are factors for the progression of renal disease. 1 The evidence in support of this hypothesis derives mostly from experimental animal studies.2-5 Most of these have focused on the tubulointerstitial space with little attention being paid to the glomerulus. The cellular response to hypoxia is largely mediated by heterodimeric transcription factors, the hypoxia-inducible factors (HIFs).2 The cellular levels of the HIF1␣ and HIF2␣ subunits (HIF␣) of HIF (gene symbols HIF1A and HIF2A) are controlled mainly by posttranslational protein modification. Under normoxia HIF␣ is degraded by the von Hippel-Lindau tumor suppressor protein. This process is regulated by oxygen-dependent hydroxylation of HIF␣ through specific prolyl hydroxylases. Under hypoxic conditions degradation of HIF␣ ceases and the stabilized protein can function as a transcription factor.2 In the renal glomerulus, a functional role of HIF1␣ 6 -8 and HIF2␣ 9 has been documented in podocytes of rodents. Recently, glomerular podocyte-specific deletion of von Hippel-Lindau tumor suppressor protein was achieved in mice, resulting in podocyte-specific overactivity of HIF with induction of HIF target genes. 6,8

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Section: Rna Isolation Preparation and Microarray Experimentsmentioning

confidence: 99%

Human Nephrosclerosis Triggers a Hypoxia-Related Glomerulopathy

Neusser

Lindenmeyer

Moll

et al. 2010

The American Journal of Pathology

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“…Comparative promoter analysis was performed for VEGF-A and EGF to identify potential similarities in the proximal promoter of VEGF-A and EGF (39). No similarities that could explain co-regulation could be identified between their promoters.…”

Section: Potential Mechanism Of Mrna Regulationmentioning

confidence: 99%

Interstitial Vascular Rarefaction and Reduced VEGF-A Expression in Human Diabetic Nephropathy

Lindenmeyer¹,

Kretzler²,

Boucherot³

et al. 2007

Journal of the American Society of Nephrology

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221

176

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Diabetic nephropathy (DN) is a frequent complication in patients with diabetes. Although the majority of DN models and human studies have focused on glomeruli, tubulointerstitial damage is a major feature of DN and an important predictor of renal dysfunction. This study sought to investigate molecular markers of pathogenic pathways in the renal interstitium of patients with DN. Microdissected tubulointerstitial compartments from biopsies with established DN and control kidneys were subjected to expression profiling. Analysis of candidate genes, potentially involved in DN on the basis of common hypotheses, identified 49 genes with significantly altered expression levels in established DN in comparison with controls. In contrast to some rodent models, the growth factors vascular endothelial growth factor A (VEGF-A) and epidermal growth factor (EGF) showed a decrease in mRNA expression in DN. This was validated on an independent cohort of patients with DN by real-time reverse transcriptase-PCR. Immunohistochemical staining for VEGF-A and EGF also showed a reduced expression in DN. The decrease of renal VEGF-A expression was associated with a reduction in peritubular capillary densities shown by platelet-endothelial cell adhesion molecule-1/CD31 staining. Furthermore, a significant inverse correlation between VEGF-A and proteinuria, as well as EGF and proteinuria, and a positive correlation between VEGF-A and hypoxia-inducible factor-1␣ mRNA was found. Thus, in human DN, a decrease of VEGF-A, rather than the reported increase as described in some rodent models, may contribute to the progressive disease. These findings and the questions about rodent models in DN raise a note of caution regarding the proposal to inhibit VEGF-A to prevent progression of DN.

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“…These modules are characterized by a set of two or more transcription factors in the same relative order and spacing working in concert in a defined functional context. This approach has been used to define coregulated podocyte slit diaphragm specific transcripts and NF-kB dependent networks in DN (for a detailed discussion of this approach see 3,5 ).…”

Section: Identifying Mechanistic Role Of Variationsmentioning

confidence: 99%

“…This review describes strategies by which the genetic etiology of nephropathy could be approached by integrating GWAS and genome-wide expression data. The use of gene expression profiling in the study of renal disease is an area of active investigation [3][4][5] . However only one publication, a study using kidney function as an indicator of aging 6 , integrates renal expression analyses with genetic association analysis.…”

Section: Introductionmentioning

confidence: 99%

Linking Variants from Genome-Wide Association Analysis to Function via Transcriptional Network Analysis

Martini

Nair

2012

Methods in Molecular Biology

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A current challenge in interpretation of Genome Wide Association studies (GWAS) is to establish the mechanistic links between the measured genotype and observed phenotype. The integration of gene expression with disease GWAS is emerging as an important strategy for deciphering these regulatory mechanisms. For renal disease, the availability of both tissue-and disease-specific expression data makes the strategy a compelling option. In this review, three approaches of integrating Single Nucleotide Polymorphism (SNP) genotypes with transcriptional regulation are discussed: (1) interpreting the functional role of transcripts affected by a SNP, (2) identifying the mechanistic role of non-coding SNPs in regulation, and (3) identifying regulatory candidate SNPs with expression associations. Combining these strategies in an integrative manner should allow the discovery of more extensive regulatory information. Linking genetics to systems biology more directly promises the opportunity to explain how genetic variants contribute to disease in a truly holistic manner.

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Comparative promoter analysis allows de novo identification of specialized cell junction-associated proteins

Cited by 113 publications

References 41 publications

Human Nephrosclerosis Triggers a Hypoxia-Related Glomerulopathy

Human Nephrosclerosis Triggers a Hypoxia-Related Glomerulopathy

Interstitial Vascular Rarefaction and Reduced VEGF-A Expression in Human Diabetic Nephropathy

Linking Variants from Genome-Wide Association Analysis to Function via Transcriptional Network Analysis

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