Systems approach identifies HIPK2 as a critical regulator of kidney tubulointerstitial fibrosis
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PROVIDER: PRJNA150661 | ENA |
REPOSITORIES: ENA
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Project description:We used an integrated computational/experimental systems biology approach to identify upstream protein kinases that regulate gene expression changes in kidneys of HIV-1 transgenic mice (Tg26), which have significant tubulo-interstitial fibrosis (TIF) and glomerulosclerosis (GS). We identified the homeo-domain interacting protein kinase 2 (HIPK2) as a key regulator of TIF and GS. HIPK2 was upregulated in kidneys of Tg26 and patients with various kidney diseases. HIV infection increased the protein level of HIPK2 by promoting oxidative stress, which inhibited Siah1-mediated proteasomal degradation of HIPK2. The data contain two sets: kidney corticies from WT and Tg26 mice and HEK293 transfected with HIPK2, HIPK2-DN and wild type.
2012-02-01 | GSE35226 | GEO
Project description:We used an integrated computational/experimental systems biology approach to identify upstream protein kinases that regulate gene expression changes in kidneys of HIV-1 transgenic mice (Tg26), which have significant tubulo-interstitial fibrosis (TIF) and glomerulosclerosis (GS). We identified the homeo-domain interacting protein kinase 2 (HIPK2) as a key regulator of TIF and GS. HIPK2 was upregulated in kidneys of Tg26 and patients with various kidney diseases. HIV infection increased the protein level of HIPK2 by promoting oxidative stress, which inhibited Siah1-mediated proteasomal degradation of HIPK2. The data contain two sets: kidney corticies from WT and Tg26 mice and HEK293 transfected with HIPK2, HIPK2-DN and wild type. Gene expression comparison between kidney cortecies of Tg26 HIV mouse model and wild type. Gene expression comparison between 293 HEK cells with HIPK-DN, HIPK-KO and normal.
2012-02-01 | E-GEOD-35226 | biostudies-arrayexpress
Project description: Not available
| S-EPMC3321097 | biostudies-literature
Project description:Homeodomain interacting protein kinase 2 (Hipk2) has previously been implicated in control of several transcription factors involved in embryonic development, apoptosis, cell proliferation and tumour development1–3. Analysis of gene expression in tissues from genetically heterogeneous mouse or human populations can reveal motifs associated with the structural or functional components of the tissue, and may predict roles for genes of unknown function4,5. Here we have applied this network strategy to uncover a novel role for the Hipk2 gene in the transcriptional system controlling adipogenesis. Both in vitro and in vivo models were used to show that knockdown or loss of Hipk2 specifically inhibits white adipose cell differentiation and tissue development. In addition, loss of Hipk2 leads to induction of pockets of multilocular brown fat-like cells in remaining white adipose depots. These cells express markers of brown and beige fat such as uncoupling protein 1 (Ucp1) and transmembrane protein 26 (Tmem26), and thermogenic genes including PPAR-γ coactivator 1a (Ppargc1a), and cell death-inducing DFFA-like effector a (Cidea). These changes are accompanied by increased insulin sensitivity in Hipk2 knock-out mice and reduced high fat diet-induced weight gain, highlighting a potential role for this kinase in diseases such as diabetes and obesity. Our study underscores the versatility and power of a readily available tissue, such as skin, for network modelling of systemic transcriptional programs involved in multiple pathways, including lipid metabolism and adipogenesis.
2014-01-01 | GSE46077 | GEO
Project description:Homeodomain interacting protein kinase 2 (Hipk2) has previously been implicated in control of several transcription factors involved in embryonic development, apoptosis, cell proliferation and tumour development1–3. Analysis of gene expression in tissues from genetically heterogeneous mouse or human populations can reveal motifs associated with the structural or functional components of the tissue, and may predict roles for genes of unknown function4,5. Here we have applied this network strategy to uncover a novel role for the Hipk2 gene in the transcriptional system controlling adipogenesis. Both in vitro and in vivo models were used to show that knockdown or loss of Hipk2 specifically inhibits white adipose cell differentiation and tissue development. In addition, loss of Hipk2 leads to induction of pockets of multilocular brown fat-like cells in remaining white adipose depots. These cells express markers of brown and beige fat such as uncoupling protein 1 (Ucp1) and transmembrane protein 26 (Tmem26), and thermogenic genes including PPAR-γ coactivator 1a (Ppargc1a), and cell death-inducing DFFA-like effector a (Cidea). These changes are accompanied by increased insulin sensitivity in Hipk2 knock-out mice and reduced high fat diet-induced weight gain, highlighting a potential role for this kinase in diseases such as diabetes and obesity. Our study underscores the versatility and power of a readily available tissue, such as skin, for network modelling of systemic transcriptional programs involved in multiple pathways, including lipid metabolism and adipogenesis. Mammary fat pads from 115 distinct untreated 8 week old [FVB/N x Spret/Ei] x FVB/N Backcross mice
2014-01-01 | E-GEOD-46077 | biostudies-arrayexpress
Project description:Background: Cardiac kinases play a critical role in the development of heart failure, and represent potential tractable therapeutic targets. However, only a very small fraction of the cardiac kinome has been investigated. To identify novel cardiac kinases involved in heart failure, we employed an integrated transcriptomics and bioinformatics analysis and identified Homeodomain-Interacting Protein Kinase 2 (HIPK2) as a novel candidate kinase. The role of HIPK2 in cardiac biology is unknown. Methods: We used the Expression2Kinase algorithm for the screening of kinase targets. To determine the role of HIPK2 in the heart, we generated cardiomyocyte-specific HIPK2 knockout (CM-KO) and heterozygous (CM-Het) mice. Heart function was examined by echocardiography and related cellular and molecular mechanisms were examined. Adeno-associated virus serotype 9 (AAV9) carrying cardiac-specific constitutively active MEK1 (TnT-MEK1-CA) were administrated to rescue cardiac dysfunction in CM-KOs. Results: To our knowledge, this is the first study to define the role of HIPK2 in cardiac biology. Using multiple HIPK2 loss-of-function mouse models, we demonstrated that reduction of HIPK2 in cardiomyocytes leads to cardiac dysfunction—suggesting a causal role in heart failure. Importantly, cardiac dysfunction in HIPK2 KOs developed with advancing age, but not during development. In addition, CM-KO and CM-Het exhibited a gene dose-response relationship of cardiomyocyte HIPK2 on heart function. HIPK2 expression in the heart was significantly reduced in human end-stage ischemic cardiomyopathy compared to non-failing myocardium, suggesting a clinical relevance of HIPK2 in cardiac biology. In vitro studies with neonatal rat ventricular cardiomyocytes corroborated the in vivo findings. Specifically, adenovirus-mediated overexpression of HIPK2 suppressed the expression of heart failure markers, NPPA and NPPB, at basal condition and abolished phenylephrine-induced pathological gene expression. An array of mechanistic studies revealed impaired ERK1/2 signaling in HIPK2 deficient hearts. In vivo rescue experiment with AAV9 TnT-MEK1-CA nearly abolished the detrimental phenotype of KOs suggesting that impaired ERK signaling mediated apoptosis as the key factor driving the detrimental phenotype in CM-KO hearts. Conclusions: Taken together, these findings suggest that cardiomyocyte HIPK2 is required to maintain normal cardiac function via ERK signaling
2019-08-27 | GSE136308 | GEO
Project description:HIPK2, a member of the homeodomain-interacting protein kinase family, is a transcriptional corepressor whose activity inhibits tumor progression and allows tumor cell apoptosis in response to chemotherapy. HIPK2 regulates the function of numerous molecules and its inhibition by siRNA, hypoxia or mutations, strongly favours molecular pathways involved in tumor progression, angiogenesis, invasion and chemoresistance. Hence the identification of novel molecules regulated by HIPK2 may be beneficial for better understanding tumor progression and for evaluating targeted antitumor therapies. By using microarray analysis, derived from HIPK2 overexpression (that mimics HIPK2 activation) in colon cancer RKO cells, we aim at evaluating the HIPK2 modulated gene expression involved in tumor progression.
2011-12-31 | E-GEOD-31089 | biostudies-arrayexpress
Project description:HIPK2, a member of the homeodomain-interacting protein kinase family, is a transcriptional corepressor whose activity inhibits tumor progression and allows tumor cell apoptosis in response to chemotherapy. HIPK2 regulates the function of numerous molecules and its inhibition by siRNA, hypoxia or mutations, strongly favours molecular pathways involved in tumor progression, angiogenesis, invasion and chemoresistance. Hence the identification of novel molecules regulated by HIPK2 may be beneficial for better understanding tumor progression and for evaluating targeted antitumor therapies.
2011-12-31 | GSE31089 | GEO
Project description:Transforming growth factor-b (TGF-b) regulates various aspects of vascular development, yet the signaling mechanisms of TGF-b in the control of angiogenesis remain poorly characterized. Here we show that homeodomain interacting protein kinases, HIPK1 and HIPK2, are transcriptional corepressors that regulate TGF-b-depednent angiogenesis during embryonic development. Loss of HIPK1 and HIPK2 leads to marked up-regulations of several potent angiogenic genes, including Vegf and Mmp10, which result in excessive endothelial proliferation and poor adherens junction formation. This robust phenotype can be recapitulated by siRNA knock down of Hipk1 and Hipk2 in human umbilical vein endothelial cells, as well as in endothelial cell-specific TGF-b type II receptor (TbRII) conditional mutants. The effects of HIPK proteins are mediated through its interaction with MEF2C and HDAC7, and this interaction can be further enhanced by TGF-b and TAK1. Remarkably, TGF-b-TAK1 signaling activates HIPK2 by phosphorylating a highly conserved tyrosine residue Y-361 within the kinase domain. Point mutation in this tyrosine completely eliminates the effect of HIPK2 in the transcriptional suppression of target genes. Together, these results reveal a previously unrecognized role of HIPK proteins in connecting TGF-b signaling pathway with the transcriptional programs for angiogenesis in early embryonic development. In this study, a total of 36,000 transcripts and ESTs (a total of 30,000 unique genes) was used to acquire expression profiles among the control, Hipk1-/-, Hipk2-/-, and Hipk1-/-;Hipk2-/- E9.5 embryos. This will allow us unsupervised and successfully to analyze the transcriptomes and finally to reveal the role of HIPK1 and HIPK2 in the signal transduction mechanism downstream of TGF-b and the transcriptional control of angiogenic gene expression during the critical stages of vascular morphogenesis.
2013-06-01 | E-GEOD-39253 | biostudies-arrayexpress
Project description:Backgrounds: The present study addressed whether V-domain Ig suppressor of T cell activation (VISTA), constitutively expressed in kidney macrophages, has a protective role in tubulointerstitial fibrotic transformation after acute antibody-mediated glomerulonephritis. Methods: Wild-type (WT) and VISTA-deficient (Vsir-/-, KO) mice were treated with nephrotoxic serum to induced acute antibody-mediated glomerulonephritis, and their cytokine and fibrosis profiles were compared. Results: VISTA was highly expressed in kidney macrophages (resident more than infiltrating subset). If VISTA was depleted, tubules suffered further damage after glomerular injury. In damaged Vsir–/– mice, the contact frequency of macrophages with infiltrated T cells increased, and then the immunometabolic characteristics of T cells changed to overproduction of interferon-γ. The Vsir–/– parenchymal tissue cells responded to this altered milieu as more producing interleukin-9, which augmented tubulointerstitial fibrosis and irreversible kidney dysfunction. The blocking antibodies against interferon-γ and interleukin-9 protected above pathological process by VISTA depletion. Conclusions: VISTA is a sentinel protein of kidney macrophages, which prevents tubulointerstitial fibrosis via interferon-γ-interleukin-9 axis after acute antibody-mediated glomerular injury.
2021-08-04 | GSE181163 | GEO