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Patient-Specific iPSC-Derived Endothelial Cells Uncover Pathways that Protect against Pulmonary Hypertension in BMPR2 Mutation Carriers.
Gu M, Shao NY, Sa S, Li D, Termglinchan V, Ameen M, Karakikes I, Sosa G, Grubert F, Lee J, Cao A, Taylor S, Ma Y, Zhao Z, Chappell J, Hamid R, Austin ED, Gold JD, Wu JC, Snyder MP, Rabinovitch M
(2017) Cell Stem Cell 20: 490-504.e5
MeSH Terms: Base Sequence, Bone Morphogenetic Protein 4, Bone Morphogenetic Protein Receptors, Type II, Cell Adhesion, Cell Movement, Cell Shape, Cell Survival, Endothelial Cells, Gene Editing, Gene Expression Regulation, Heterozygote, Humans, Hypertension, Pulmonary, Induced Pluripotent Stem Cells, Mutation, Neovascularization, Physiologic, Phosphorylation, Sequence Analysis, RNA, Signal Transduction, Smad Proteins, p38 Mitogen-Activated Protein Kinases
Show Abstract · Added February 21, 2017
In familial pulmonary arterial hypertension (FPAH), the autosomal dominant disease-causing BMPR2 mutation is only 20% penetrant, suggesting that genetic variation provides modifiers that alleviate the disease. Here, we used comparison of induced pluripotent stem cell-derived endothelial cells (iPSC-ECs) from three families with unaffected mutation carriers (UMCs), FPAH patients, and gender-matched controls to investigate this variation. Our analysis identified features of UMC iPSC-ECs related to modifiers of BMPR2 signaling or to differentially expressed genes. FPAH-iPSC-ECs showed reduced adhesion, survival, migration, and angiogenesis compared to UMC-iPSC-ECs and control cells. The "rescued" phenotype of UMC cells was related to an increase in specific BMPR2 activators and/or a reduction in inhibitors, and the improved cell adhesion could be attributed to preservation of related signaling. The improved survival was related to increased BIRC3 and was independent of BMPR2. Our findings therefore highlight protective modifiers for FPAH that could help inform development of future treatment strategies.
Copyright © 2017 Elsevier Inc. All rights reserved.
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21 MeSH Terms
EGF receptor deletion in podocytes attenuates diabetic nephropathy.
Chen J, Chen JK, Harris RC
(2015) J Am Soc Nephrol 26: 1115-25
MeSH Terms: Albuminuria, Animals, Caspase 3, Diabetic Nephropathies, ErbB Receptors, Hyperglycemia, Male, Mice, Knockout, Podocytes, Proto-Oncogene Proteins c-bcl-2, Reactive Oxygen Species, Signal Transduction, Smad Proteins, Receptor-Regulated, Transforming Growth Factor beta, src-Family Kinases
Show Abstract · Added October 27, 2014
The generation of reactive oxygen species (ROS), particularly superoxide, by damaged or dysfunctional mitochondria has been postulated to be an initiating event in the development of diabetes complications. The glomerulus is a primary site of diabetic injury, and podocyte injury is a classic hallmark of diabetic glomerular lesions. In streptozotocin-induced type 1 diabetes, podocyte-specific EGF receptor (EGFR) knockout mice (EGFR(podKO)) and their wild-type (WT) littermates had similar levels of hyperglycemia and polyuria, but EGFR(podKO) mice had significantly less albuminuria and less podocyte loss compared with WT diabetic mice. Furthermore, EGFR(podKO) diabetic mice had less TGF-β1 expression, Smad2/3 phosphorylation, and glomerular fibronectin deposition. Immunoblotting of isolated glomerular lysates revealed that the upregulation of cleaved caspase 3 and downregulation of Bcl2 in WT diabetic mice were attenuated in EGFR(podKO) diabetic mice. Administration of the SOD mimetic mito-tempol or the NADPH oxidase inhibitor apocynin attenuated the upregulation of p-c-Src, p-EGFR, p-ERK1/2, p-Smad2/3, and TGF-β1 expression and prevented the alteration of cleaved caspase 3 and Bcl2 expression in glomeruli of WT diabetic mice. High-glucose treatment of cultured mouse podocytes induced similar alterations in the production of ROS; phosphorylation of c-Src, EGFR, and Smad2/3; and expression of TGF-β1, cleaved caspase 3, and Bcl2. These alterations were inhibited by treatment with mito-tempol or apocynin or by inhibiting EGFR expression or activity. Thus, results of our studies utilizing mice with podocyte-specific EGFR deletion demonstrate that EGFR activation has a major role in activating pathways that mediate podocyte injury and loss in diabetic nephropathy.
Copyright © 2015 by the American Society of Nephrology.
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15 MeSH Terms
Integrin-mediated type II TGF-β receptor tyrosine dephosphorylation controls SMAD-dependent profibrotic signaling.
Chen X, Wang H, Liao HJ, Hu W, Gewin L, Mernaugh G, Zhang S, Zhang ZY, Vega-Montoto L, Vanacore RM, Fässler R, Zent R, Pozzi A
(2014) J Clin Invest 124: 3295-310
MeSH Terms: Animals, Collagen, Epithelial-Mesenchymal Transition, Fibrosis, Integrin alpha1, Integrin alpha1beta1, Kidney, Male, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Knockout, Phosphorylation, Protein Tyrosine Phosphatase, Non-Receptor Type 2, Protein-Serine-Threonine Kinases, Receptor, Transforming Growth Factor-beta Type II, Receptors, Transforming Growth Factor beta, Signal Transduction, Smad Proteins, Smad2 Protein, Smad3 Protein, Tyrosine, Ureteral Obstruction
Show Abstract · Added October 27, 2014
Tubulointerstitial fibrosis underlies all forms of end-stage kidney disease. TGF-β mediates both the development and the progression of kidney fibrosis through binding and activation of the serine/threonine kinase type II TGF-β receptor (TβRII), which in turn promotes a TβRI-mediated SMAD-dependent fibrotic signaling cascade. Autophosphorylation of serine residues within TβRII is considered the principal regulatory mechanism of TβRII-induced signaling; however, there are 5 tyrosine residues within the cytoplasmic tail that could potentially mediate TβRII-dependent SMAD activation. Here, we determined that phosphorylation of tyrosines within the TβRII tail was essential for SMAD-dependent fibrotic signaling within cells of the kidney collecting duct. Conversely, the T cell protein tyrosine phosphatase (TCPTP) dephosphorylated TβRII tail tyrosine residues, resulting in inhibition of TβR-dependent fibrotic signaling. The collagen-binding receptor integrin α1β1 was required for recruitment of TCPTP to the TβRII tail, as mice lacking this integrin exhibited impaired TCPTP-mediated tyrosine dephosphorylation of TβRII that led to severe fibrosis in a unilateral ureteral obstruction model of renal fibrosis. Together, these findings uncover a crosstalk between integrin α1β1 and TβRII that is essential for TβRII-mediated SMAD activation and fibrotic signaling pathways.
2 Communities
4 Members
1 Resources
23 MeSH Terms
BMP pathway regulation of and by macrophages.
Talati M, West J, Zaynagetdinov R, Hong CC, Han W, Blackwell T, Robinson L, Blackwell TS, Lane K
(2014) PLoS One 9: e94119
MeSH Terms: Animals, Bone Morphogenetic Protein Receptors, Type II, Cells, Cultured, Coculture Techniques, Hypertension, Pulmonary, Macrophages, Mice, Mice, Transgenic, Muscle, Smooth, Vascular, Myocytes, Smooth Muscle, Signal Transduction, Smad Proteins
Show Abstract · Added April 10, 2014
Pulmonary arterial hypertension (PAH) is a disease of progressively increasing pulmonary vascular resistance, associated with mutations of the type 2 receptor for the BMP pathway, BMPR2. The canonical signaling pathway for BMPR2 is through the SMAD family of transcription factors. BMPR2 is expressed in every cell type, but the impact of BMPR2 mutations affecting SMAD signaling, such as Bmpr2delx4+, had only previously been investigated in smooth muscle and endothelium. In the present study, we created a mouse with universal doxycycline-inducible expression of Bmpr2delx4+ in order to determine if broader expression had an impact relevant to the development of PAH. We found that the most obvious phenotype was a dramatic, but patchy, increase in pulmonary inflammation. We crossed these double transgenic mice onto an NF-κB reporter strain, and by luciferase assays on live mice, individual organs and isolated macrophages, we narrowed down the origin of the inflammatory phenotype to constitutive activation of tissue macrophages. Study of bone marrow-derived macrophages from mutant and wild-type mice suggested a baseline difference in differentiation state in Bmpr2 mutants. When activated with LPS, both mutant and wild-type macrophages secrete BMP pathway inhibitors sufficient to suppress BMP pathway activity in smooth muscle cells (SMC) treated with conditioned media. Functionally, co-culture with macrophages results in a BMP signaling-dependent increase in scratch closure in cultured SMC. We conclude that SMAD signaling through BMP is responsible, in part, for preventing macrophage activation in both live animals and in cells in culture, and that activated macrophages secrete BMP inhibitors in sufficient quantity to cause paracrine effect on vascular smooth muscle.
2 Communities
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12 MeSH Terms
Deficiency of retinaldehyde dehydrogenase 1 induces BMP2 and increases bone mass in vivo.
Nallamshetty S, Wang H, Rhee EJ, Kiefer FW, Brown JD, Lotinun S, Le P, Baron R, Rosen CJ, Plutzky J
(2013) PLoS One 8: e71307
MeSH Terms: Adipogenesis, Aldehyde Dehydrogenase, Alkaline Phosphatase, Animals, Bone Density, Bone Morphogenetic Protein 2, Core Binding Factor Alpha 1 Subunit, Female, Femur, Gene Expression Regulation, Insulin-Like Growth Factor I, Mice, Mice, Inbred C57BL, Mice, Knockout, Radiography, Signal Transduction, Smad Proteins, Tibia, Tretinoin
Show Abstract · Added September 6, 2016
The effects of retinoids, the structural derivatives of vitamin A (retinol), on post-natal peak bone density acquisition and skeletal remodeling are complex and compartment specific. Emerging data indicates that retinoids, such as all trans retinoic acid (ATRA) and its precursor all trans retinaldehyde (Rald), exhibit distinct and divergent transcriptional effects in metabolism. Despite these observations, the role of enzymes that control retinoid metabolism in bone remains undefined. In this study, we examined the skeletal phenotype of mice deficient in retinaldehyde dehydrogenase 1 (Aldh1a1), the enzyme responsible for converting Rald to ATRA in adult animals. Bone densitometry and micro-computed tomography (µCT) demonstrated that Aldh1a1-deficient (Aldh1a1(-/-) ) female mice had higher trabecular and cortical bone mass compared to age and sex-matched control C57Bl/6 wild type (WT) mice at multiple time points. Histomorphometry confirmed increased cortical bone thickness and demonstrated significantly higher bone marrow adiposity in Aldh1a1(-/-) mice. In serum assays, Aldh1a1(-/-) mice also had higher serum IGF-1 levels. In vitro, primary Aldh1a1(-/-) mesenchymal stem cells (MSCs) expressed significantly higher levels of bone morphogenetic protein 2 (BMP2) and demonstrated enhanced osteoblastogenesis and adipogenesis versus WT MSCs. BMP2 was also expressed at higher levels in the femurs and tibias of Aldh1a1(-/-) mice with accompanying induction of BMP2-regulated responses, including expression of Runx2 and alkaline phosphatase, and Smad phosphorylation. In vitro, Rald, which accumulates in Aldh1a1(-/-) mice, potently induced BMP2 in WT MSCs in a retinoic acid receptor (RAR)-dependent manner, suggesting that Rald is involved in the BMP2 increases seen in Aldh1a1 deficiency in vivo. Collectively, these data implicate Aldh1a1 as a novel determinant of cortical bone density and marrow adiposity in the skeleton in vivo through modulation of BMP signaling.
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19 MeSH Terms
Disruption of canonical TGFβ-signaling in murine coronary progenitor cells by low level arsenic.
Allison P, Huang T, Broka D, Parker P, Barnett JV, Camenisch TD
(2013) Toxicol Appl Pharmacol 272: 147-53
MeSH Terms: Animals, Arsenites, Blotting, Western, Cell Differentiation, Cell Line, Cell Survival, Coronary Vessels, Epithelial-Mesenchymal Transition, Fluorescent Antibody Technique, Indicators and Reagents, Mesenchymal Stem Cells, Mice, Microfilament Proteins, Muscle Proteins, Myocytes, Smooth Muscle, Signal Transduction, Smad Proteins, Stem Cells, Transforming Growth Factor beta
Show Abstract · Added February 21, 2016
Exposure to arsenic results in several types of cancers as well as heart disease. A major contributor to ischemic heart pathologies is coronary artery disease, however the influences by environmental arsenic in this disease process are not known. Similarly, the impact of toxicants on blood vessel formation and function during development has not been studied. During embryogenesis, the epicardium undergoes proliferation, migration, and differentiation into several cardiac cell types including smooth muscle cells which contribute to the coronary vessels. The TGFβ family of ligands and receptors is essential for developmental cardiac epithelial to mesenchymal transition (EMT) and differentiation into coronary smooth muscle cells. In this in vitro study, 18hour exposure to 1.34μM arsenite disrupted developmental EMT programming in murine epicardial cells causing a deficit in cardiac mesenchyme. The expression of EMT genes including TGFβ2, TGFβ receptor-3, Snail, and Has-2 are decreased in a dose-dependent manner following exposure to arsenite. TGFβ2 cell signaling is abrogated as detected by decreases in phosphorylated Smad2/3 when cells are exposed to 1.34μM arsenite. There is also loss of nuclear accumulation pSmad due to arsenite exposure. These observations coincide with a decrease in vimentin positive mesenchymal cells invading three-dimensional collagen gels. However, arsenite does not block TGFβ2 mediated smooth muscle cell differentiation by epicardial cells. Overall these results show that arsenic exposure blocks developmental EMT gene programming in murine coronary progenitor cells by disrupting TGFβ2 signals and Smad activation, and that smooth muscle cell differentiation is refractory to this arsenic toxicity.
Published by Elsevier Inc.
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19 MeSH Terms
Bone morphogenetic protein type I receptor antagonists decrease growth and induce cell death of lung cancer cell lines.
Langenfeld E, Hong CC, Lanke G, Langenfeld J
(2013) PLoS One 8: e61256
MeSH Terms: Bone Morphogenetic Protein 2, Bone Morphogenetic Protein Receptors, Type I, Bronchi, Cell Death, Cell Line, Tumor, Cell Proliferation, Cell Survival, Clone Cells, Endothelial Cells, Epithelial Cells, Gene Knockdown Techniques, Humans, Inhibitor of Differentiation Proteins, Lung Neoplasms, Pyrazoles, Pyrimidines, Signal Transduction, Smad Proteins
Show Abstract · Added September 20, 2013
Bone morphogenetic proteins (BMPs) are highly conserved morphogens that are essential for normal development. BMP-2 is highly expressed in the majority of non-small cell lung carcinomas (NSCLC) but not in normal lung tissue or benign lung tumors. The effects of the BMP signaling cascade on the growth and survival of cancer cells is poorly understood. We show that BMP signaling is basally active in lung cancer cell lines, which can be effectively inhibited with selective antagonists of the BMP type I receptors. Lung cancer cell lines express alk2, alk3, and alk6 and inhibition of a single BMP receptor was not sufficient to decrease signaling. Inhibition of more than one type I receptor was required to decrease BMP signaling in lung cancer cell lines. BMP receptor antagonists and silencing of BMP type I receptors with siRNA induced cell death, inhibited cell growth, and caused a significant decrease in the expression of inhibitor of differentiation (Id1, Id2, and Id3) family members, which are known to regulate cell growth and survival in many types of cancers. BMP receptor antagonists also decreased clonogenic cell growth. Knockdown of Id3 significantly decreased cell growth and induced cell death of lung cancer cells. H1299 cells stably overexpressing Id3 were resistant to growth suppression and induction of cell death induced by the BMP antagonist DMH2. These studies suggest that BMP signaling promotes cell growth and survival of lung cancer cells, which is mediated through its regulation of Id family members. Selective antagonists of the BMP type I receptors represents a potential means to pharmacologically treat NSCLC and other carcinomas with an activated BMP signaling cascade.
1 Communities
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18 MeSH Terms
Deleting the TGF-β receptor attenuates acute proximal tubule injury.
Gewin L, Vadivelu S, Neelisetty S, Srichai MB, Paueksakon P, Pozzi A, Harris RC, Zent R
(2012) J Am Soc Nephrol 23: 2001-11
MeSH Terms: Acute Kidney Injury, Animals, Apoptosis, Kidney Cortex, Kidney Tubules, Proximal, Male, Mercuric Chloride, Mice, Protein-Serine-Threonine Kinases, Receptor, Transforming Growth Factor-beta Type II, Receptors, Transforming Growth Factor beta, Smad Proteins, Transforming Growth Factor beta
Show Abstract · Added February 24, 2014
TGF-β is a profibrotic growth factor in CKD, but its role in modulating the kidney's response to AKI is not well understood. The proximal tubule epithelial cell, which is the main cellular target of AKI, expresses high levels of both TGF-β and its receptors. To determine how TGF-β signaling in this tubular segment affects the response to AKI, we selectively deleted the TGF-β type II receptor in the proximal tubules of mice. This deletion attenuated renal impairment and reduced tubular apoptosis in mercuric chloride-induced injury. In vitro, deficiency of the TGF-β type II receptor protected proximal tubule epithelial cells from hydrogen peroxide-induced apoptosis, which was mediated in part by Smad-dependent signaling. Taken together, these results suggest that TGF-β signaling in the proximal tubule has a detrimental effect on the response to AKI as a result of its proapoptotic effects.
1 Communities
4 Members
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13 MeSH Terms
Transforming growth factor β suppresses osteoblast differentiation via the vimentin activating transcription factor 4 (ATF4) axis.
Lian N, Lin T, Liu W, Wang W, Li L, Sun S, Nyman JS, Yang X
(2012) J Biol Chem 287: 35975-84
MeSH Terms: Activating Transcription Factor 4, Animals, COS Cells, Cell Differentiation, Cell Line, Tumor, Cercopithecus aethiops, Mice, Mice, Knockout, Osteoblasts, Osteocalcin, Phosphatidylinositol 3-Kinases, Proto-Oncogene Proteins c-akt, Rats, Signal Transduction, Smad Proteins, TOR Serine-Threonine Kinases, Transcription, Genetic, Transforming Growth Factor beta, Up-Regulation, Vimentin
Show Abstract · Added October 31, 2013
ATF4 is an osteoblast-enriched transcription factor of the leucine zipper family. We recently identified that vimentin, a leucine zipper-containing intermediate filament protein, suppresses ATF4-dependent osteocalcin (Ocn) transcription and osteoblast differentiation. Here we show that TGFβ inhibits ATF4-dependent activation of Ocn by up-regulation of vimentin expression. Osteoblasts lacking Atf4 (Atf4(-/-)) were less sensitive than wild-type (WT) cells to the inhibition by TGFβ on alkaline phosphatase activity, Ocn transcription and mineralization. Importantly, the anabolic effect of a monoclonal antibody neutralizing active TGFβ ligands on bone in WT mice was blunted in Atf4(-/-) mice. These data establish that ATF4 is required for TGFβ-related suppression of Ocn transcription and osteoblast differentiation in vitro and in vivo. Interestingly, TGFβ did not directly regulate the expression of ATF4; instead, it enhanced the expression of vimentin, a negative regulator of ATF4, at the post-transcriptional level. Accordingly, knockdown of endogenous vimentin in 2T3 osteoblasts abolished the inhibition of Ocn transcription by TGFβ, confirming an indirect mechanism by which TGFβ acts through vimentin to suppress ATF4-dependent Ocn activation. Furthermore, inhibition of PI3K/Akt/mTOR signaling, but not canonical Smad signaling, downstream of TGFβ, blocked TGFβ-induced synthesis of vimentin, and inhibited ATF4-dependent Ocn transcription in osteoblasts. Thus, our study identifies that TGFβ stimulates vimentin production via PI3K-Akt-mTOR signaling, which leads to suppression of ATF4-dependent Ocn transcription and osteoblast differentiation.
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20 MeSH Terms
BMP2 signals loss of epithelial character in epicardial cells but requires the Type III TGFβ receptor to promote invasion.
Hill CR, Sanchez NS, Love JD, Arrieta JA, Hong CC, Brown CB, Austin AF, Barnett JV
(2012) Cell Signal 24: 1012-22
MeSH Terms: Adaptor Proteins, Signal Transducing, Animals, Bone Morphogenetic Protein 2, Carrier Proteins, Cell Differentiation, Cell Movement, Cells, Cultured, Coronary Vessels, Epithelial Cells, Epithelial-Mesenchymal Transition, Mice, Mice, Knockout, Myocytes, Smooth Muscle, Neuropeptides, Pericardium, Proteoglycans, Receptors, Transforming Growth Factor beta, Smad Proteins, Transforming Growth Factors
Show Abstract · Added August 19, 2012
Coronary vessel development depends on a subpopulation of epicardial cells that undergo epithelial to mesenchymal transformation (EMT) and invade the subepicardial space and myocardium. These cells form the smooth muscle of the vessels and fibroblasts, but the mechanisms that regulate these processes are poorly understood. Mice lacking the Type III Transforming Growth Factor β Receptor (TGFβR3) die by E14.5 due to failed coronary vessel development accompanied by reduced epicardial cell invasion. BMP2 signals via TGFβR3 emphasizing the importance of determining the relative contributions of the canonical BMP signaling pathway and TGFβR3-dependent signaling to BMP2 responsiveness. Here we examined the role of TGFβR3 in BMP2 signaling in epicardial cells. Whereas TGFβ induced loss of epithelial character and smooth muscle differentiation, BMP2 induced an ALK3-dependent loss of epithelial character and modestly inhibited TGFβ-stimulated differentiation. Tgfbr3(-/-) cells respond to BMP2 indicating that TGFβR3 is not required. However, Tgfbr3(-/-) cells show decreased invasion in response to BMP2 and overexpression of TGFβR3 in Tgfbr3(-/-) cells rescued invasion. Invasion was dependent on ALK5, ALK2, ALK3, and Smad4. Expression of TGFβR3 lacking the 3 C-terminal amino acids required to interact with the scaffolding protein GIPC (GAIP-interacting protein, C terminus) did not rescue. Knockdown of GIPC in Tgfbr3(+/+) or Tgfbr3(-/-) cells rescued with TGFβR3 decreased BMP2-stimulated invasion confirming a requirement for TGFβR3/GIPC interaction. Our results reveal the relative roles of TGFβR3-dependent and TGFβR3-independent signaling in the actions of BMP2 on epicardial cell behavior and demonstrate the critical role of TGFβR3 in mediating BMP2-stimulated invasion.
Copyright © 2011 Elsevier Inc. All rights reserved.
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19 MeSH Terms