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Article ; Online: Tracing the footsteps of glomerular insulin signaling in diabetic kidney disease.

Chang, Gene-Yuan / Park, Ae Seo Deok / Susztak, Katalin

2011 Volume 79, Issue 8, Page(s) 802–804

Abstract: Insufficient insulin secretion and insulin resistance are hallmarks of diabetes. Recent studies indicate that insulin plays an important role in maintaining the glomerular filtration barrier. Mima et al. report that glomeruli of diabetic and obese rats ... ...

Abstract	Insufficient insulin secretion and insulin resistance are hallmarks of diabetes. Recent studies indicate that insulin plays an important role in maintaining the glomerular filtration barrier. Mima et al. report that glomeruli of diabetic and obese rats suffer from insulin resistance and altered insulin signaling. Protein kinase C inhibitors are able to overcome insulin resistance, offering new hopes for the treatment of the condition.
MeSH term(s)	Animals ; Diabetic Nephropathies/drug therapy ; Diabetic Nephropathies/etiology ; Diabetic Nephropathies/physiopathology ; Disease Models, Animal ; Humans ; Insulin/physiology ; Insulin Resistance ; Kidney Glomerulus/physiopathology ; Protein Kinase C/antagonists & inhibitors ; Rats ; Signal Transduction
Chemical Substances	Insulin ; Protein Kinase C (EC 2.7.11.13)
Language	English
Publishing date	2011-03-30
Publishing country	United States
Document type	Comment ; Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	120573-0
ISSN	1523-1755 ; 0085-2538
ISSN (online)	1523-1755
ISSN	0085-2538
DOI	10.1038/ki.2010.559
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Article ; Online: Diet-Induced Podocyte Dysfunction in Drosophila and Mammals.

Na, Jianbo / Sweetwyne, Mariya T / Park, Ae Seo Deok / Susztak, Katalin / Cagan, Ross L

Cell reports

2015 Volume 12, Issue 4, Page(s) 636–647

Abstract: Diabetic nephropathy is a major cause of end-stage kidney disease. Characterized by progressive microvascular disease, most efforts have focused on injury to the glomerular endothelium. Recent work has suggested a role for the podocyte, a highly ... ...

Abstract	Diabetic nephropathy is a major cause of end-stage kidney disease. Characterized by progressive microvascular disease, most efforts have focused on injury to the glomerular endothelium. Recent work has suggested a role for the podocyte, a highly specialized component of the glomerular filtration barrier. Here, we demonstrate that the Drosophila nephrocyte, a cell analogous to the mammalian podocyte, displays defects that phenocopy aspects of diabetic nephropathy in animals fed chronic high dietary sucrose. Through functional studies, we identify an OGT-Polycomb-Knot-Sns pathway that links dietary sucrose to loss of the Nephrin ortholog Sns. Reducing OGT through genetic or drug means is sufficient to rescue loss of Sns, leading to overall extension of lifespan. We demonstrate upregulation of the Knot ortholog EBF2 in glomeruli of human diabetic nephropathy patients and a mouse ob/ob diabetes model. Furthermore, we demonstrate rescue of Nephrin expression and cell viability in ebf2(-/-) primary podocytes cultured in high glucose.
MeSH term(s)	Animals ; Basic Helix-Loop-Helix Transcription Factors/genetics ; Basic Helix-Loop-Helix Transcription Factors/metabolism ; Cells, Cultured ; Diabetic Nephropathies/etiology ; Diabetic Nephropathies/metabolism ; Diabetic Nephropathies/pathology ; Dietary Carbohydrates/adverse effects ; Drosophila/genetics ; Drosophila/metabolism ; Drosophila Proteins/genetics ; Drosophila Proteins/metabolism ; Humans ; Immunoglobulins/genetics ; Immunoglobulins/metabolism ; Membrane Proteins/genetics ; Membrane Proteins/metabolism ; Mice ; N-Acetylglucosaminyltransferases/genetics ; N-Acetylglucosaminyltransferases/metabolism ; Podocytes/metabolism ; Podocytes/pathology ; Podocytes/physiology ; Sucrose/toxicity
Chemical Substances	Basic Helix-Loop-Helix Transcription Factors ; Dietary Carbohydrates ; Drosophila Proteins ; Immunoglobulins ; Membrane Proteins ; SNS protein, Drosophila ; nephrin ; Sucrose (57-50-1) ; N-Acetylglucosaminyltransferases (EC 2.4.1.-) ; UDP-N-acetylglucosamine-peptide beta-N-acetylglucosaminyltransferase (EC 2.4.1.-)
Language	English
Publishing date	2015-07-16
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2649101-1
ISSN	2211-1247 ; 2211-1247
ISSN (online)	2211-1247
ISSN	2211-1247
DOI	10.1016/j.celrep.2015.06.056
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Article ; Online: Kidney cytosine methylation changes improve renal function decline estimation in patients with diabetic kidney disease.

Gluck, Caroline / Qiu, Chengxiang / Han, Sang Youb / Palmer, Matthew / Park, Jihwan / Ko, Yi-An / Guan, Yuting / Sheng, Xin / Hanson, Robert L / Huang, Jing / Chen, Yong / Park, Ae Seo Deok / Izquierdo, Maria Concepcion / Mantzaris, Ioannis / Verma, Amit / Pullman, James / Li, Hongzhe / Susztak, Katalin

Nature communications

2019 Volume 10, Issue 1, Page(s) 2461

Abstract: Epigenetic changes might provide the biological explanation for the long-lasting impact of metabolic alterations of diabetic kidney disease development. Here we examined cytosine methylation of human kidney tubules using Illumina Infinium 450 K arrays ... ...

Abstract	Epigenetic changes might provide the biological explanation for the long-lasting impact of metabolic alterations of diabetic kidney disease development. Here we examined cytosine methylation of human kidney tubules using Illumina Infinium 450 K arrays from 91 subjects with and without diabetes and varying degrees of kidney disease using a cross-sectional design. We identify cytosine methylation changes associated with kidney structural damage and build a model for kidney function decline. We find that the methylation levels of 65 probes are associated with the degree of kidney fibrosis at genome wide significance. In total 471 probes improve the model for kidney function decline. Methylation probes associated with kidney damage and functional decline enrich on kidney regulatory regions and associate with gene expression changes, including epidermal growth factor (EGF). Altogether, our work shows that kidney methylation differences can be detected in patients with diabetic kidney disease and improve kidney function decline models indicating that they are potentially functionally important.
MeSH term(s)	Aged ; Case-Control Studies ; CpG Islands ; Cross-Sectional Studies ; Cytosine/metabolism ; DNA Methylation ; Diabetic Nephropathies/genetics ; Diabetic Nephropathies/metabolism ; Diabetic Nephropathies/pathology ; Disease Progression ; Epigenesis, Genetic ; Female ; Fibrosis ; Gene Expression Regulation ; Glomerular Filtration Rate ; Humans ; Kidney/metabolism ; Kidney/pathology ; Male ; Middle Aged
Chemical Substances	Cytosine (8J337D1HZY)
Language	English
Publishing date	2019-06-05
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-019-10378-8
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Article ; Online: Functional genomic annotation of genetic risk loci highlights inflammation and epithelial biology networks in CKD.

Ledo, Nora / Ko, Yi-An / Park, Ae-Seo Deok / Kang, Hyun-Mi / Han, Sang-Youb / Choi, Peter / Susztak, Katalin

Journal of the American Society of Nephrology : JASN

2014 Volume 26, Issue 3, Page(s) 692–714

Abstract: Genome-wide association studies (GWASs) have identified multiple loci associated with the risk of CKD. Almost all risk variants are localized to the noncoding region of the genome; therefore, the role of these variants in CKD development is largely ... ...

Abstract	Genome-wide association studies (GWASs) have identified multiple loci associated with the risk of CKD. Almost all risk variants are localized to the noncoding region of the genome; therefore, the role of these variants in CKD development is largely unknown. We hypothesized that polymorphisms alter transcription factor binding, thereby influencing the expression of nearby genes. Here, we examined the regulation of transcripts in the vicinity of CKD-associated polymorphisms in control and diseased human kidney samples and used systems biology approaches to identify potentially causal genes for prioritization. We interrogated the expression and regulation of 226 transcripts in the vicinity of 44 single nucleotide polymorphisms using RNA sequencing and gene expression arrays from 95 microdissected control and diseased tubule samples and 51 glomerular samples. Gene expression analysis from 41 tubule samples served for external validation. 92 transcripts in the tubule compartment and 34 transcripts in glomeruli showed statistically significant correlation with eGFR. Many novel genes, including ACSM2A/2B, FAM47E, and PLXDC1, were identified. We observed that the expression of multiple genes in the vicinity of any single CKD risk allele correlated with renal function, potentially indicating that genetic variants influence multiple transcripts. Network analysis of GFR-correlating transcripts highlighted two major clusters; a positive correlation with epithelial and vascular functions and an inverse correlation with inflammatory gene cluster. In summary, our functional genomics analysis highlighted novel genes and critical pathways associated with kidney function for future analysis.
MeSH term(s)	Case-Control Studies ; Genome-Wide Association Study ; Humans ; Inflammation/metabolism ; Kidney Glomerulus/metabolism ; Polymorphism, Genetic ; Renal Insufficiency, Chronic/genetics ; Renal Insufficiency, Chronic/metabolism ; Uromodulin/genetics ; Urothelium/metabolism
Chemical Substances	UMOD protein, human ; Uromodulin
Language	English
Publishing date	2014-09-17
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	1085942-1
ISSN	1533-3450 ; 1046-6673
ISSN (online)	1533-3450
ISSN	1046-6673
DOI	10.1681/ASN.2014010028
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Article ; Online: Human Kidney Tubule-Specific Gene Expression Based Dissection of Chronic Kidney Disease Traits.

Beckerman, Pazit / Qiu, Chengxiang / Park, Jihwan / Ledo, Nora / Ko, Yi-An / Park, Ae-Seo Deok / Han, Sang-Youb / Choi, Peter / Palmer, Matthew / Susztak, Katalin

EBioMedicine

2017 Volume 24, Page(s) 267–276

Abstract: Chronic kidney disease (CKD) has diverse phenotypic manifestations including structural (such as fibrosis) and functional (such as glomerular filtration rate and albuminuria) alterations. Gene expression profiling has recently gained popularity as an ... ...

Abstract	Chronic kidney disease (CKD) has diverse phenotypic manifestations including structural (such as fibrosis) and functional (such as glomerular filtration rate and albuminuria) alterations. Gene expression profiling has recently gained popularity as an important new tool for precision medicine approaches. Here we used unbiased and directed approaches to understand how gene expression captures different CKD manifestations in patients with diabetic and hypertensive CKD. Transcriptome data from ninety-five microdissected human kidney samples with a range of demographics, functional and structural changes were used for the primary analysis. Data obtained from 41 samples were available for validation. Using the unbiased Weighted Gene Co-Expression Network Analysis (WGCNA) we identified 16 co-expressed gene modules. We found that modules that strongly correlated with eGFR primarily encoded genes with metabolic functions. Gene groups that mainly encoded T-cell receptor and collagen pathways, showed the strongest correlation with fibrosis level, suggesting that these two phenotypic manifestations might have different underlying mechanisms. Linear regression models were then used to identify genes whose expression showed significant correlation with either structural (fibrosis) or functional (eGFR) manifestation and mostly corroborated the WGCNA findings. We concluded that gene expression is a very sensitive sensor of fibrosis, as the expression of 1654 genes correlated with fibrosis even after adjusting to eGFR and other clinical parameters. The association between GFR and gene expression was mostly mediated by fibrosis. In conclusion, our transcriptome-based CKD trait dissection analysis suggests that the association between gene expression and renal function is mediated by structural changes and that there may be differences in pathways that lead to decline in kidney function and the development of fibrosis, respectively.
MeSH term(s)	Aged ; Diabetes Mellitus, Type 2/complications ; Diabetes Mellitus, Type 2/genetics ; Female ; Gene Expression Profiling/methods ; Gene Expression Regulation ; Gene Regulatory Networks ; Glomerular Filtration Rate ; Humans ; Hypertension/complications ; Hypertension/genetics ; Kidney Tubules/chemistry ; Kidney Tubules/pathology ; Kidney Tubules/physiopathology ; Male ; Middle Aged ; Oligonucleotide Array Sequence Analysis ; Organ Specificity ; Regression Analysis ; Renal Insufficiency, Chronic/genetics ; Renal Insufficiency, Chronic/pathology ; Renal Insufficiency, Chronic/physiopathology
Language	English
Publishing date	2017-09-18
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	2851331-9
ISSN	2352-3964
ISSN (online)	2352-3964
DOI	10.1016/j.ebiom.2017.09.014
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Article ; Online: Transcriptome analysis of human diabetic kidney disease.

Woroniecka, Karolina I / Park, Ae Seo Deok / Mohtat, Davoud / Thomas, David B / Pullman, James M / Susztak, Katalin

Diabetes

2011 Volume 60, Issue 9, Page(s) 2354–2369

Abstract: Objective: Diabetic kidney disease (DKD) is the single leading cause of kidney failure in the U.S., for which a cure has not yet been found. The aim of our study was to provide an unbiased catalog of gene-expression changes in human diabetic kidney ... ...

Abstract	Objective: Diabetic kidney disease (DKD) is the single leading cause of kidney failure in the U.S., for which a cure has not yet been found. The aim of our study was to provide an unbiased catalog of gene-expression changes in human diabetic kidney biopsy samples. Research design and methods: Affymetrix expression arrays were used to identify differentially regulated transcripts in 44 microdissected human kidney samples. DKD samples were significant for their racial diversity and decreased glomerular filtration rate (~25-35 mL/min). Stringent statistical analysis, using the Benjamini-Hochberg corrected two-tailed t test, was used to identify differentially expressed transcripts in control and diseased glomeruli and tubuli. Two different web-based algorithms were used to define differentially regulated pathways. Results: We identified 1,700 differentially expressed probesets in DKD glomeruli and 1,831 in diabetic tubuli, and 330 probesets were commonly differentially expressed in both compartments. Pathway analysis highlighted the regulation of Ras homolog gene family member A, Cdc42, integrin, integrin-linked kinase, and vascular endothelial growth factor signaling in DKD glomeruli. The tubulointerstitial compartment showed strong enrichment for inflammation-related pathways. The canonical complement signaling pathway was determined to be statistically differentially regulated in both DKD glomeruli and tubuli and was associated with increased glomerulosclerosis even in a different set of DKD samples. Conclusions: Our studies have cataloged gene-expression regulation and identified multiple novel genes and pathways that may play a role in the pathogenesis of DKD or could serve as biomarkers.
MeSH term(s)	Adult ; Aged ; Cross-Sectional Studies ; Diabetic Nephropathies/genetics ; Diabetic Nephropathies/metabolism ; Diabetic Nephropathies/pathology ; Female ; Gene Expression Profiling ; Gene Expression Regulation ; Humans ; Kidney Glomerulus/metabolism ; Kidney Glomerulus/pathology ; Male ; Middle Aged
Language	English
Publishing date	2011-07-13
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	80085-5
ISSN	1939-327X ; 0012-1797
ISSN (online)	1939-327X
ISSN	0012-1797
DOI	10.2337/db10-1181
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Article ; Online: Defective fatty acid oxidation in renal tubular epithelial cells has a key role in kidney fibrosis development.

Kang, Hyun Mi / Ahn, Seon Ho / Choi, Peter / Ko, Yi-An / Han, Seung Hyeok / Chinga, Frank / Park, Ae Seo Deok / Tao, Jianling / Sharma, Kumar / Pullman, James / Bottinger, Erwin P / Goldberg, Ira J / Susztak, Katalin

Nature medicine

2014 Volume 21, Issue 1, Page(s) 37–46

Abstract: Renal fibrosis is the histological manifestation of a progressive, usually irreversible process causing chronic and end-stage kidney disease. We performed genome-wide transcriptome studies of a large cohort (n = 95) of normal and fibrotic human kidney ... ...

Abstract	Renal fibrosis is the histological manifestation of a progressive, usually irreversible process causing chronic and end-stage kidney disease. We performed genome-wide transcriptome studies of a large cohort (n = 95) of normal and fibrotic human kidney tubule samples followed by systems and network analyses and identified inflammation and metabolism as the top dysregulated pathways in the diseased kidneys. In particular, we found that humans and mouse models with tubulointerstitial fibrosis had lower expression of key enzymes and regulators of fatty acid oxidation (FAO) and higher intracellular lipid deposition compared to controls. In vitro experiments indicated that inhibition of FAO in tubule epithelial cells caused ATP depletion, cell death, dedifferentiation and intracellular lipid deposition, phenotypes observed in fibrosis. In contrast, restoring fatty acid metabolism by genetic or pharmacological methods protected mice from tubulointerstitial fibrosis. Our results raise the possibility that correcting the metabolic defect in FAO may be useful for preventing and treating chronic kidney disease.
MeSH term(s)	Animals ; Epithelial Cells/metabolism ; Epithelial Cells/pathology ; Fatty Acids/genetics ; Fatty Acids/metabolism ; Fibrosis/genetics ; Fibrosis/metabolism ; Fibrosis/pathology ; Gene Expression Profiling ; Gene Expression Regulation ; Humans ; Inflammation/genetics ; Inflammation/metabolism ; Inflammation/pathology ; Kidney Diseases/genetics ; Kidney Diseases/metabolism ; Kidney Diseases/pathology ; Kidney Tubules/metabolism ; Kidney Tubules/pathology ; Mice ; Oxidation-Reduction ; Signal Transduction/genetics
Chemical Substances	Fatty Acids
Language	English
Publishing date	2014-12-01
Publishing country	United States
Document type	Journal Article
ZDB-ID	1220066-9
ISSN	1546-170X ; 1078-8956
ISSN (online)	1546-170X
ISSN	1078-8956
DOI	10.1038/nm.3762
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Zs.A 4212: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Adiponectin promotes functional recovery after podocyte ablation.

Rutkowski, Joseph M / Wang, Zhao V / Park, Ae Seo Deok / Zhang, Jianning / Zhang, Dihua / Hu, Ming Chang / Moe, Orson W / Susztak, Katalin / Scherer, Philipp E

Journal of the American Society of Nephrology : JASN

2013 Volume 24, Issue 2, Page(s) 268–282

Abstract: Low levels of the adipocyte-secreted protein adiponectin correlate with albuminuria in both mice and humans, but whether adiponectin has a causative role in modulating renal disease is unknown. Here, we first generated a mouse model that allows induction ...

Abstract	Low levels of the adipocyte-secreted protein adiponectin correlate with albuminuria in both mice and humans, but whether adiponectin has a causative role in modulating renal disease is unknown. Here, we first generated a mouse model that allows induction of caspase-8-mediated apoptosis specifically in podocytes upon injection of a construct-specific agent. These POD-ATTAC mice exhibited significant kidney damage, mimicking aspects of human renal disease, such as foot process effacement, mesangial expansion, and glomerulosclerosis. After the initial induction, both podocytes and filtration function recovered. Next, we crossed POD-ATTAC mice with mice lacking or overexpressing adiponectin. POD-ATTAC mice lacking adiponectin developed irreversible albuminuria and renal failure; conversely, POD-ATTAC mice overexpressing adiponectin recovered more rapidly and exhibited less interstitial fibrosis. In conclusion, these results suggest that adiponectin is a renoprotective protein after podocyte injury. Furthermore, the POD-ATTAC mouse provides a platform for further studies, allowing precise timing of podocyte injury and regeneration.
MeSH term(s)	Acetates/pharmacology ; Adiponectin/genetics ; Adiponectin/pharmacology ; Albuminuria/drug therapy ; Albuminuria/pathology ; Albuminuria/physiopathology ; Animals ; Apoptosis/physiology ; Caspase 3/metabolism ; Caspase 8/metabolism ; Disease Models, Animal ; Dose-Response Relationship, Drug ; Female ; Fibrosis/drug therapy ; Fibrosis/pathology ; Fibrosis/physiopathology ; Glomerular Filtration Barrier/drug effects ; Glomerular Filtration Barrier/pathology ; Glomerular Filtration Barrier/physiology ; Humans ; Indoles/pharmacology ; Male ; Mice ; Mice, Inbred Strains ; Mice, Knockout ; PPAR gamma/antagonists & inhibitors ; Podocytes/pathology ; Podocytes/physiology ; Recovery of Function/drug effects ; Recovery of Function/physiology ; Renal Insufficiency, Chronic/drug therapy ; Renal Insufficiency, Chronic/pathology ; Renal Insufficiency, Chronic/physiopathology
Chemical Substances	2-(2-(4-phenoxy-2-propylphenoxy)ethyl)indole-5-acetic acid ; Acetates ; Adiponectin ; Adipoq protein, mouse ; Indoles ; PPAR gamma ; Casp3 protein, mouse (EC 3.4.22.-) ; Casp8 protein, mouse (EC 3.4.22.-) ; Caspase 3 (EC 3.4.22.-) ; Caspase 8 (EC 3.4.22.-)
Language	English
Publishing date	2013-01-18
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	1085942-1
ISSN	1533-3450 ; 1046-6673
ISSN (online)	1533-3450
ISSN	1046-6673
DOI	10.1681/ASN.2012040414
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Article ; Online: Transgenic expression of human APOL1 risk variants in podocytes induces kidney disease in mice.

Beckerman, Pazit / Bi-Karchin, Jing / Park, Ae Seo Deok / Qiu, Chengxiang / Dummer, Patrick D / Soomro, Irfana / Boustany-Kari, Carine M / Pullen, Steven S / Miner, Jeffrey H / Hu, Chien-An A / Rohacs, Tibor / Inoue, Kazunori / Ishibe, Shuta / Saleem, Moin A / Palmer, Matthew B / Cuervo, Ana Maria / Kopp, Jeffrey B / Susztak, Katalin

Nature medicine

2017 Volume 23, Issue 4, Page(s) 429–438

Abstract: African Americans have a heightened risk of developing chronic and end-stage kidney disease, an association that is largely attributed to two common genetic variants, termed G1 and G2, in the APOL1 gene. Direct evidence demonstrating that these APOL1 ... ...

Abstract	African Americans have a heightened risk of developing chronic and end-stage kidney disease, an association that is largely attributed to two common genetic variants, termed G1 and G2, in the APOL1 gene. Direct evidence demonstrating that these APOL1 risk alleles are pathogenic is still lacking because the APOL1 gene is present in only some primates and humans; thus it has been challenging to demonstrate experimental proof of causality of these risk alleles for renal disease. Here we generated mice with podocyte-specific inducible expression of the APOL1 reference allele (termed G0) or each of the risk-conferring alleles (G1 or G2). We show that mice with podocyte-specific expression of either APOL1 risk allele, but not of the G0 allele, develop functional (albuminuria and azotemia), structural (foot-process effacement and glomerulosclerosis) and molecular (gene-expression) changes that closely resemble human kidney disease. Disease development was cell-type specific and likely reversible, and the severity correlated with the level of expression of the risk allele. We further found that expression of the risk-variant APOL1 alleles interferes with endosomal trafficking and blocks autophagic flux, which ultimately leads to inflammatory-mediated podocyte death and glomerular scarring. In summary, this is the first demonstration that the expression of APOL1 risk alleles is causal for altered podocyte function and glomerular disease in vivo.
MeSH term(s)	Albuminuria/genetics ; Alleles ; Animals ; Apolipoprotein L1 ; Apolipoproteins/genetics ; Autophagy/genetics ; Azotemia/genetics ; Blotting, Western ; Endocytosis/genetics ; Endosomes/metabolism ; Fluorescent Antibody Technique ; Genetic Predisposition to Disease ; Genetic Variation ; Glomerulosclerosis, Focal Segmental/genetics ; Glomerulosclerosis, Focal Segmental/pathology ; HEK293 Cells ; HeLa Cells ; Humans ; Immunohistochemistry ; In Situ Nick-End Labeling ; Kidney Glomerulus/metabolism ; Kidney Glomerulus/pathology ; Kidney Glomerulus/ultrastructure ; Lipoproteins, HDL/genetics ; Mice ; Mice, Transgenic ; Microscopy, Electron ; Podocytes/metabolism ; Podocytes/ultrastructure ; Renal Insufficiency, Chronic/genetics ; Renal Insufficiency, Chronic/pathology
Chemical Substances	APOL1 protein, human ; Apolipoprotein L1 ; Apolipoproteins ; Lipoproteins, HDL
Language	English
Publishing date	2017-02-20
Publishing country	United States
Document type	Journal Article
ZDB-ID	1220066-9
ISSN	1546-170X ; 1078-8956
ISSN (online)	1546-170X
ISSN	1078-8956
DOI	10.1038/nm.4287
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Article: Cytosine methylation changes in enhancer regions of core pro-fibrotic genes characterize kidney fibrosis development

Ko, Yi-An / Mohtat, Davoud / Suzuki, Masako / Park, Ae Seo Deok / Izquierdo, Maria Concepcion / Han, Sang Youb / Kang, Hyun Mi / Si, Han / Hostetter, Thomas / Pullman, James M / Fazzari, Melissa / Verma, Amit / Zheng, Deyou / Greally, John M / Susztak, Katalin

Genome biology. 2013 Oct., v. 14, no. 10

2013

Abstract: BACKGROUND: One in eleven people is affected by chronic kidney disease, a condition characterized by kidney fibrosis and progressive loss of kidney function. Epidemiological studies indicate that adverse intrauterine and postnatal environments have a ... ...

Abstract	BACKGROUND: One in eleven people is affected by chronic kidney disease, a condition characterized by kidney fibrosis and progressive loss of kidney function. Epidemiological studies indicate that adverse intrauterine and postnatal environments have a long-lasting role in chronic kidney disease development. Epigenetic information represents a plausible carrier for mediating this programming effect. Here we demonstrate that genome-wide cytosine methylation patterns of healthy and chronic kidney disease tubule samples obtained from patients show significant differences. RESULTS: We identify differentially methylated regions and validate these in a large replication dataset. The differentially methylated regions are rarely observed on promoters, but mostly overlap with putative enhancer regions, and they are enriched in consensus binding sequences for important renal transcription factors. This indicates their importance in gene expression regulation. A core set of genes that are known to be related to kidney fibrosis, including genes encoding collagens, show cytosine methylation changes correlating with downstream transcript levels. CONCLUSIONS: Our report raises the possibility that epigenetic dysregulation plays a role in chronic kidney disease development via influencing core pro-fibrotic pathways and can aid the development of novel biomarkers and future therapeutics.
Keywords	DNA methylation ; biomarkers ; data collection ; epidemiological studies ; epigenetics ; fibrosis ; gene expression regulation ; genes ; kidneys ; patients ; renal function ; therapeutics ; transcription factors
Language	English
Dates of publication	2013-10
Size	p. 3159.
Publishing place	Springer-Verlag
Document type	Article
ZDB-ID	2040529-7
ISSN	1474-760X ; 1465-6914 ; 1465-6906
ISSN (online)	1474-760X ; 1465-6914
ISSN	1465-6906
DOI	10.1186/gb-2013-14-10-r108
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In stock of ZB MED Cologne/Königswinter

Order via subito

More links

Kategorien

Order via subito