Effect of deletion of von-Hippel-Lindau (VHL) in the proximal tubule in diabetic kidney disease
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE210401 | GEO | 2022/08/08
REPOSITORIES: GEO
Similar Datasets
Project description:Effect of deletion of von-Hippel-Lindau (VHL) in the proximal tubule in diabetic kidney disease
| PRJNA865585 | ENA
Project description:The cellular response to low oxygen supply is mediated by hypoxia-inducible factors (HIF). Under hypoxic conditions, HIF is stabilized and target genes are induced. Under normoxia, however, HIF is ubiquitinated through the von Hippel-Lindau protein (VHL), which results in proteasomal degradation. HIF activation leads to induction of genes involved in erythropoiesis, angiogenesis, and cell survival. Furthermore, HIF orchestrates a metabolic shift from oxidative phosphorylation to glycolysis to facilitate ATP production under low oxygen conditions. We used microarrays to detail gene expression changes in kidneys with stable HIF activation in renal tubules, which was achieved by tubule-specific VHL ablation.
2014-01-17 | GSE54172 | GEO
Project description:The cellular response to low oxygen supply is mediated by hypoxia-inducible factors (HIF). Under hypoxic conditions, HIF is stabilized and target genes are induced. Under normoxia, however, HIF is ubiquitinated through the von Hippel-Lindau protein (VHL), which results in proteasomal degradation. HIF activation leads to induction of genes involved in erythropoiesis, angiogenesis, and cell survival. Furthermore, HIF orchestrates a metabolic shift from oxidative phosphorylation to glycolysis to facilitate ATP production under low oxygen conditions. We used microarrays to detail gene expression changes in kidneys with stable HIF activation in renal tubules, which was achieved by tubule-specific VHL ablation. Three week old Pax8-rtTA;LC-1;Vhl-floxed mice (n=4) and control littermates (n=4) were treated with doxycyline in drinking water for two weeks and put back on normal drinking water for one week. Six weeks old mice were sacrificed and kidneys harvested. Total RNA was extracted and hybridized on Affymetrix microarrays.
2014-01-17 | E-GEOD-54172 | biostudies-arrayexpress
Project description:Von Hippel-Lindau (VHL) gene mutations induce neural tissue hemangioblastomas as well as highly vascularized clear cell renal cell carcinomas (ccRCCs). Pathological vessel remodeling arises from mis-regulation of hypoxia inducible factors and vascular endothelial growth factor, among other genes. Variation in disease penetrance has long been recognized in relation to genotype. We show Vhl mutations also disrupt Notch signaling, causing mutation-specific vascular abnormalities e.g. type 1 (null) vs. type 2B (murine G518A representing human R167Q). In conditional mutation retina vasculature, Vhl null mutation (i.e. UBCCreER/+; Vhlfl/fl) had little effect on initial vessel branching, but severely reduced arterial and venous branching at later stages. Interestingly, this mutation accelerated arterial maturation, as observed in retina vessel morphology and aberrant a-smooth muscle actin localization, particularly in vascular pericytes. RNA sequencing analysis identified gene expression changes within several key pathways including Notch and smooth muscle cell contractility. Notch inhibition failed to reverse later-stage branching defects but rescued the accelerated arterialization. Retinal vessels harboring the type 2B Vhl mutation (i.e. UBCCreER/+; Vhlfl/2B) displayed stage-specific changes in vessel branching and an advanced progression toward an arterial phenotype. Disrupting Notch signaling in 2B mutants increased both artery and vein branching, and restored arterial maturation toward non-mutant levels. By revealing differential effects of the null and type 2B Vhl mutations on vessel branching and maturation, these data may provide insight into the variability of VHL-associated vascular changes, particularly the heterogeneity and aggressiveness in ccRCC vessel growth, as well as suggest Notch pathway targets for treating VHL syndrome.
2019-08-20 | GSE109102 | GEO
Project description:Von Hippel-Lindau (VHL) mutations disrupt vascular patterning and maturation via Notch
| PRJNA429643 | ENA
Project description:We have generated two zebrafish lines carrying inactivating germline mutations in the von Hippel-Lindau (VHL) tumor suppressor gene ortholog vhl. Mutant embryos display a general systemic hypoxic response, including the upregulation of hypoxia-induced genes by 1 day post-fertilization and a severe hyperventilation and cardiophysiological response. vhl mutants develop polycythemia with concomitantly increased epo/epor mRNA levels and Epo signaling. In situ hybridizations reveal global up-regulation of both red and white hematopoietic lineages. Hematopoietic tissues are highly proliferative, with enlarged populations of c-myb+ HSCs and circulating erythroid precursors. Chemical activation of Hif-signaling recapitulated aspects of the vhl-/- phenotype. Furthermore, microarray expression analysis confirms the hypoxic response and hematopoietic phenotype observed in vhl-/- embryos. We conclude that Vhl participates in regulating hematopoiesis and erythroid differentiation. Injections with human VHLp30 and R200W mutant mRNA demonstrate functional conservation of VHL between mammals and zebrafish at the amino acid level, indicating that vhl mutants are a powerful new tool to study genotype-phenotype correlations in human disease. Zebrafish mutants are the first congenital embryonic viable systemic vertebrate animal model for VHL, representing the most accurate model for VHL-associated polycythemia to date. They will contribute to our understanding of hypoxic signaling, hematopoiesis and VHL-associated disease progression.
2009-03-01 | GSE14866 | GEO
Project description:Understanding the nature of the various glucose-derived signals for insulin secretion (both triggering and amplifying) is essential for gaining insight into the functional failure of the beta-cells in diabetes and the development of drugs for correcting this problem. The beta-cells uniquely couple changes in cellular metabolism to electrical activity and thus insulin release. In mice, beta-cell specific deletion of the von Hippel-Lindau (VHL) tumor suppressor protein leads to the activation of a HIF transcription program that includes genes involved in glycolysis, suppression of mitochondrial activity and lactate production. This reprogramming of cellular metabolism results in abnormal insulin secretion properties. Experiment Overall Design: Three batches of isolated islets from each genotype where used for RNA isolation and Affymetrix measurements.
2008-11-22 | E-GEOD-11484 | biostudies-arrayexpress
Project description:We and others have previously shown that glomerular endothelial cells and podocytes express hypoxia-inducible transcription factors (HIFs). HIFs bind to hypoxia response elements in target genes, such as vascular endothelial growth factor, which is continually produced by podocytes throughout life. To further assess function of HIFs in podocyte biology, podocin-Cre mice were mated with floxed von Hippel-Lindau (VHL) mice to selectively delete VHL, a component of an E3 ligase complex responsible for degradation of HIFs in normoxia. We reasoned that cells lacking VHL would overexpress stable HIFs and upregulate hypoxia-responsive genes. Progeny from these crosses displayed two phenotypes, non-proteinuric with glomerular basement membrane (GBM) defects and proteinuric with GBM defects and end-stage renal failure at ~6 months of age. Gene changes associated with the mild, non-proteinuric phenotype were studied using isolated glomeruli from wildtype and Pod-Cre fVHL mice.
2010-08-03 | GSE20235 | GEO
Project description:The endothelial landscape and its role in von Hippel-Lindau disease
| PRJNA751917 | ENA
Project description:The von Hippel-Lindau (VHL) tumor suppressor functions as a ubiquitin ligase that mediates proteolytic inactivation of hydroxylated a subunits of hypoxia-inducible factor (HIF). Although studies of VHL defective renal carcinoma cells suggest the existence of other VHL tumor suppressor pathways, dysregulation of the HIF transcriptional cascade has extensive effects that make it difficult to distinguish whether, and to what extent, observed abnormalities in these cells represent effects on pathways that are distinct from HIF. Here, we report on a genetic analysis of HIF dependent and independent effects of VHL inactivation by studying gene expression patterns in C. elegans. We show tight conservation of the HIF-1/VHL-1/EGL-9 hydroxylase pathway. However, persisting differential gene expression in hif-1 versus hif-1; vhl-1 double mutant worms clearly distinguished HIF-1 independent effects of VHL-1 inactivation. Genomic clustering, predicted functional similarities, and a common pattern of dysregulation in both vhl-1 worms and a set of mutants (dpy-18, let-268, gon-1, mig-17 and unc-6), with different defects in extracellular matrix formation, suggest that dysregulation of these genes reflects a discrete HIF-1 independent function of VHL-1 that is connected with extracellular matrix function. Set of arrays organized by shared biological context, such as organism, tumors types, processes, etc. Bishop T, Lau KW, Epstein AC, Kim SK, Jiang M, O'rourke D, Pugh CW, Gleadle JM, Taylor MS, Hodgkin J, Ratcliffe PJ, Genetic Analysis of Pathways Regulated by the von Hippel-Lindau Tumor Suppressor in Caenorhabditis elegans., Bishop T, et al. (2004) PLoS Biol 2(10):e289, 2004-10-01, http://biology.plosjournals.org/plosonline/?request=get-document&doi=10.1371/journal.pbio.0020289 Computed
2005-07-20 | E-GEOD-2963 | biostudies-arrayexpress