Modular Activation of Nuclear Factor-κB Transcriptional Programs in Human Diabetic Nephropathy

Schmid, Holger; Boucherot, Anissa; Yasuda, Yoshinari; Henger, Anna; Brunner, Bodo; Eichinger, Felix; Nitsche, Almut; Kiss, Éva; Bleich, Markus; Gröne, Hermann Josef; Nelson, Peter J.; Schlöndorff, Detlef; Cohen, Clemens D.; Kretzler, Matthias

doi:10.2337/db06-0477

Cited by 399 publications

(381 citation statements)

References 31 publications

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“…Previous high-throughput strategies have relied on mouse (Endlich et al 2002;Brunskill et al 2011;Jain et al 2011) or human (Saleem et al 2008) immortalized glomerular visceral epithelial cells, but in vitro culture leads to rapid loss of both lineagespecific phenotypes and lineage-specific gene expression. Wholetissue-based molecular profiles of renal disease are attainable Higgins et al 2004;Schmid et al 2006;Bennett et al 2007;Ju et al 2009;Hodgin et al 2010;Lindenmeyer et al 2010;Woroniecka et al 2011) since human renal tissue is routinely obtained by diagnostic fine needle biopsy, but wholetissue expression profiles have not previously been capable of identifying gene expression at the cell-lineage level. This difficulty is not unique to renal disease.…”

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confidence: 99%

Defining cell-type specificity at the transcriptional level in human disease

et al. 2013

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Cell-lineage–specific transcripts are essential for differentiated tissue function, implicated in hereditary organ failure, and mediate acquired chronic diseases. However, experimental identification of cell-lineage–specific genes in a genome-scale manner is infeasible for most solid human tissues. We developed the first genome-scale method to identify genes with cell-lineage–specific expression, even in lineages not separable by experimental microdissection. Our machine-learning–based approach leverages high-throughput data from tissue homogenates in a novel iterative statistical framework. We applied this method to chronic kidney disease and identified transcripts specific to podocytes, key cells in the glomerular filter responsible for hereditary and most acquired glomerular kidney disease. In a systematic evaluation of our predictions by immunohistochemistry, our in silico approach was significantly more accurate (65% accuracy in human) than predictions based on direct measurement of in vivo fluorescence-tagged murine podocytes (23%). Our method identified genes implicated as causal in hereditary glomerular disease and involved in molecular pathways of acquired and chronic renal diseases. Furthermore, based on expression analysis of human kidney disease biopsies, we demonstrated that expression of the podocyte genes identified by our approach is significantly related to the degree of renal impairment in patients. Our approach is broadly applicable to define lineage specificity in both cell physiology and human disease contexts. We provide a user-friendly website that enables researchers to apply this method to any cell-lineage or tissue of interest. Identified cell-lineage–specific transcripts are expected to play essential tissue-specific roles in organogenesis and disease and can provide starting points for the development of organ-specific diagnostics and therapies.

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confidence: 99%

Defining cell-type specificity at the transcriptional level in human disease

et al. 2013

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“…[12][13][14] Recently, we have combined a large-scale gene expression profiling with a systems biology approach to study the transcriptional response of isolated PTEC in proteinuric glomerulopathies. 8 In a study performed by Schmid and coworkers, 15 microarray technology and systems biology tools have also been successfully applied to differentiate the tubulointerstitial transcriptional response in human diabetic nephropathy as compared with nondiabetic samples. However, in this study, no microdissection of specific cells was performed.…”

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confidence: 99%

Hypoxia response and VEGF-A expression in human proximal tubular epithelial cells in stable and progressive renal disease

Rudnicki

Perco

Enrich

et al. 2009

Laboratory Investigation

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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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Modular Activation of Nuclear Factor-κB Transcriptional Programs in Human Diabetic Nephropathy

Cited by 399 publications

References 31 publications

Defining cell-type specificity at the transcriptional level in human disease

Defining cell-type specificity at the transcriptional level in human disease

Hypoxia response and VEGF-A expression in human proximal tubular epithelial cells in stable and progressive renal disease

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

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