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1.
Nat Commun ; 10(1): 3303, 2019 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-31341160

RESUMO

The mechanisms driving the development of extracapillary lesions in focal segmental glomerulosclerosis (FSGS) and crescentic glomerulonephritis (CGN) remain poorly understood. A key question is how parietal epithelial cells (PECs) invade glomerular capillaries, thereby promoting injury and kidney failure. Here we show that expression of the tetraspanin CD9 increases markedly in PECs in mouse models of CGN and FSGS, and in kidneys from individuals diagnosed with these diseases. Cd9 gene targeting in PECs prevents glomerular damage in CGN and FSGS mouse models. Mechanistically, CD9 deficiency prevents the oriented migration of PECs into the glomerular tuft and their acquisition of CD44 and ß1 integrin expression. These findings highlight a critical role for de novo expression of CD9 as a common pathogenic switch driving the PEC phenotype in CGN and FSGS, while offering a potential therapeutic avenue to treat these conditions.

2.
Eur Heart J ; 40(26): 2142-2151, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-31098611

RESUMO

AIMS: We aimed to evaluate the frequency, clinical features, and prognostic implications of cardiac arrest (CA) in takotsubo syndrome (TTS). METHODS AND RESULTS: We reviewed the records of patients with CA and known heart rhythm from the International Takotsubo Registry. The main outcomes were 60-day and 5-year mortality. In addition, predictors of mortality and predictors of CA during the acute TTS phase were assessed. Of 2098 patients, 103 patients with CA and known heart rhythm during CA were included. Compared with patients without CA, CA patients were more likely to be younger, male, and have apical TTS, atrial fibrillation (AF), neurologic comorbidities, physical triggers, and longer corrected QT-interval and lower left ventricular ejection fraction on admission. In all, 57.1% of patients with CA at admission had ventricular fibrillation/tachycardia, while 73.7% of patients with CA in the acute phase had asystole/pulseless electrical activity. Patients with CA showed higher 60-day (40.3% vs. 4.0%, P < 0.001) and 5-year mortality (68.9% vs. 16.7%, P < 0.001) than patients without CA. T-wave inversion and intracranial haemorrhage were independently associated with higher 60-day mortality after CA, whereas female gender was associated with lower 60-day mortality. In the acute phase, CA occurred less frequently in females and more frequently in patients with AF, ST-segment elevation, and higher C-reactive protein on admission. CONCLUSIONS: Cardiac arrest is relatively frequent in TTS and is associated with higher short- and long-term mortality. Clinical and electrocardiographic parameters independently predicted mortality after CA.

3.
Nephrol Ther ; 15 Suppl 1: S1-S5, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30981386

RESUMO

The publisher regrets that this article has been temporarily removed. A replacement will appear as soon as possible in which the reason for the removal of the article will be specified, or the article will be reinstated. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our-business/policies/article-withdrawal .

4.
Eur Heart J ; 40(9): 768-784, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30657897

RESUMO

AIMS: Hypertension is common. Recent data suggest that macrophages (Mφ) contribute to, and protect from, hypertension. Endothelin-1 (ET-1) is the most potent endogenous vasoconstrictor with additional pro-inflammatory properties. We investigated the role of the ET system in experimental and clinical hypertension by modifying Mφ number and phenotype. METHODS AND RESULTS: In vitro, Mφ ET receptor function was explored using pharmacological, gene silencing, and knockout approaches. Using the CD11b-DTR mouse and novel mice with myeloid cell-specific endothelin-B (ETB) receptor deficiency (LysMETB-/-), we explored the effects of modifying Mφ number and phenotype on the hypertensive effects of ET-1, angiotensin II (ANG II), a model that is ET-1 dependent, and salt. In patients with small vessel vasculitis, the impacts of Mφ depleting and non-depleting therapies on blood pressure (BP) and endothelial function were examined. Mouse and human Mφ expressed both endothelin-A and ETB receptors and displayed chemokinesis to ET-1. However, stimulation of Mφ with exogenous ET-1 did not polarize Mφ phenotype. Interestingly, both mouse and human Mφ cleared ET-1 through ETB receptor mediated, and dynamin-dependent, endocytosis. Mφ depletion resulted in an augmented chronic hypertensive response to both ET-1 and salt. LysMETB-/- mice displayed an exaggerated hypertensive response to both ET-1 and ANG II. Finally, in patients who received Mφ depleting immunotherapy BP was higher and endothelial function worse than in those receiving non-depleting therapies. CONCLUSION: Mφ and ET-1 may play an important role in BP control and potentially have a critical role as a therapeutic target in hypertension.

5.
Nat Commun ; 8(1): 1829, 2017 11 28.
Artigo em Inglês | MEDLINE | ID: mdl-29184126

RESUMO

Crescentic rapidly progressive glomerulonephritis (RPGN) represents the most aggressive form of acquired glomerular disease. While most therapeutic approaches involve potentially toxic immunosuppressive strategies, the pathophysiology remains incompletely understood. Podocytes are glomerular epithelial cells that are normally growth-arrested because of the expression of cyclin-dependent kinase (CDK) inhibitors. An exception is in RPGN where podocytes undergo a deregulation of their differentiated phenotype and proliferate. Here we demonstrate that microRNA-92a (miR-92a) is enriched in podocytes of patients and mice with RPGN. The CDK inhibitor p57Kip2 is a major target of miR-92a that constitutively safeguards podocyte cell cycle quiescence. Podocyte-specific deletion of miR-92a in mice de-repressed the expression of p57Kip2 and prevented glomerular injury in RPGN. Administration of an anti-miR-92a after disease initiation prevented albuminuria and kidney failure, indicating miR-92a inhibition as a potential therapeutic strategy for RPGN. We demonstrate that miRNA induction in epithelial cells can break glomerular tolerance to immune injury.


Assuntos
Glomerulonefrite/tratamento farmacológico , Glomerulonefrite/patologia , MicroRNAs/antagonistas & inibidores , Podócitos/citologia , Adolescente , Adulto , Idoso , Animais , Antagomirs/farmacologia , Ciclo Celular/efeitos dos fármacos , Ciclo Celular/fisiologia , Diferenciação Celular/fisiologia , Proliferação de Células/fisiologia , Inibidor de Quinase Dependente de Ciclina p57/metabolismo , Inibidor de Quinase Dependente de Ciclina p57/farmacologia , Quinases Ciclina-Dependentes/metabolismo , Feminino , Deleção de Genes , Perfilação da Expressão Gênica , Glomerulonefrite/genética , Glomerulonefrite/metabolismo , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/genética , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Podócitos/efeitos dos fármacos , Podócitos/metabolismo , Adulto Jovem
6.
J Am Soc Nephrol ; 28(12): 3563-3578, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28928136

RESUMO

FSGS, the most common primary glomerular disorder causing ESRD, is a complex disease that is only partially understood. Progressive sclerosis is a hallmark of FSGS, and genetic tracing studies have shown that parietal epithelial cells participate in the formation of sclerotic lesions. The loss of podocytes triggers a focal activation of parietal epithelial cells, which subsequently form cellular adhesions with the capillary tuft. However, in the absence of intrinsic podocyte alterations, the origin of the pathogenic signal that triggers parietal epithelial cell recruitment remains elusive. In this study, investigation of the role of the endothelial PAS domain-containing protein 1 (EPAS1), a regulatory α subunit of the hypoxia-inducible factor complex, during angiotensin II-induced hypertensive nephropathy provided novel insights into FSGS pathogenesis in the absence of a primary podocyte abnormality. We infused angiotensin II into endothelial-selective Epas1 knockout mice and their littermate controls. Although the groups presented with identical high BP, endothelial-specific Epas1 gene deletion accentuated albuminuria with severe podocyte lesions and recruitment of pathogenic parietal glomerular epithelial cells. These lesions and dysfunction of the glomerular filtration barrier were associated with FSGS in endothelial Epas1-deficient mice only. These results indicate that endothelial EPAS1 has a global protective role during glomerular hypertensive injuries without influencing the hypertensive effect of angiotensin II. Furthermore, these findings provide proof of principle that endothelial-derived signaling can trigger FSGS and illustrate the potential importance of the EPAS1 endothelial transcription factor in secondary FSGS.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Células Epiteliais/citologia , Regulação da Expressão Gênica , Glomerulosclerose Segmentar e Focal/metabolismo , Hipertensão/metabolismo , Glomérulos Renais/metabolismo , Albuminas/análise , Angiotensina II/metabolismo , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/deficiência , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Pressão Sanguínea , Diferenciação Celular , Cruzamentos Genéticos , Progressão da Doença , Células Epiteliais/metabolismo , Deleção de Genes , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Podócitos/metabolismo , Telemetria
7.
Haematologica ; 102(7): 1161-1172, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28385784

RESUMO

Although the primary origin of sickle cell disease is a hemoglobin disorder, many types of cells contribute considerably to the pathophysiology of the disease. The adhesion of neutrophils to activated endothelium is critical in the pathophysiology of sickle cell disease and targeting neutrophils and their interactions with endothelium represents an important opportunity for the development of new therapeutics. We focused on endothelin-1, a mediator involved in neutrophil activation and recruitment in tissues, and investigated the involvement of the endothelin receptors in the interaction of neutrophils with endothelial cells. We used fluorescence intravital microscopy analyses of the microcirculation in sickle mice and quantitative microfluidic fluorescence microscopy of human blood. Both experiments on the mouse model and patients indicate that blocking endothelin receptors, particularly ETB receptor, strongly influences neutrophil recruitment under inflammatory conditions in sickle cell disease. We show that human neutrophils have functional ETB receptors with calcium signaling capability, leading to increased adhesion to the endothelium through effects on both endothelial cells and neutrophils. Intact ETB function was found to be required for tumor necrosis factor α-dependent upregulation of CD11b on neutrophils. Furthermore, we confirmed that human neutrophils synthesize endothelin-1, which may be involved in autocrine and paracrine pathophysiological actions. Thus, the endothelin-ETB axis should be considered as a cytokine-like potent pro-inflammatory pathway in sickle cell disease. Blockade of endothelin receptors, including ETB, may provide major benefits for preventing or treating vaso-occlusive crises in sickle cell patients.


Assuntos
Anemia Falciforme/metabolismo , Adesão Celular , Endotélio Vascular/metabolismo , Neutrófilos/metabolismo , Receptor de Endotelina B/metabolismo , Adolescente , Anemia Falciforme/sangue , Anemia Falciforme/genética , Anemia Falciforme/terapia , Animais , Antígeno CD11b/metabolismo , Cálcio/metabolismo , Estudos de Casos e Controles , Adesão Celular/efeitos dos fármacos , Sobrevivência Celular , Criança , Pré-Escolar , Modelos Animais de Doenças , Células Endoteliais/metabolismo , Antagonistas do Receptor de Endotelina A/farmacologia , Antagonistas do Receptor de Endotelina B/farmacologia , Endotelina-1/metabolismo , Hemodinâmica/efeitos dos fármacos , Humanos , Contagem de Leucócitos , Migração e Rolagem de Leucócitos , Antígeno de Macrófago 1/metabolismo , Camundongos , Ativação de Neutrófilo , Neutrófilos/imunologia , Receptor de Endotelina A/metabolismo , Migração Transendotelial e Transepitelial/efeitos dos fármacos , Migração Transendotelial e Transepitelial/imunologia , Fator de Necrose Tumoral alfa/metabolismo
8.
J Diabetes Res ; 2017: 9603924, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29359167

RESUMO

Objective: Indirect evidence suggests a role for heme oxygenase-1 (HO-1) in limiting diabetic vasculopathy. The goal of this study was to assess the role of HO-1 in the development of microvascular lesions within glomeruli during diabetes mellitus using a mouse model with specific alteration of the Hmox1 gene. Approach and Results: The effects of Hmox1 haploinsufficiency were studied as a means of assessing the intrinsic contribution of HO-1 in the development of renal microvascular lesions during diabetes. Renal function and histology were analyzed 10 weeks after diabetes induction with streptozotocin. Diabetic Hmox1+/- mice showed higher levels of albuminuria and blood urea compared to their wild-type diabetic littermates. More severe glomerular microvascular lesions were also observed in the diabetic Hmox1+/- mice. This was associated with a renal increase in the expression of the oxidative stress marker, nitrotyrosine. Conclusions: Genetic Hmox1 partial deficiency is sufficient to sensitize mice to the development of diabetic glomerular microvascular lesions. HO-1 exerts antioxidant effects in the kidney during diabetes mellitus. These have protective effects on the development of glomerular endothelial injury.


Assuntos
Diabetes Mellitus Experimental/complicações , Angiopatias Diabéticas/metabolismo , Nefropatias Diabéticas/metabolismo , Heme Oxigenase-1/genética , Glomérulos Renais/metabolismo , Proteínas de Membrana/genética , Estresse Oxidativo/genética , Ácido Peroxinitroso/metabolismo , Animais , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/metabolismo , Angiopatias Diabéticas/genética , Angiopatias Diabéticas/patologia , Nefropatias Diabéticas/genética , Nefropatias Diabéticas/patologia , Endotélio Vascular/metabolismo , Endotélio Vascular/patologia , Predisposição Genética para Doença , Rim/irrigação sanguínea , Rim/metabolismo , Rim/patologia , Glomérulos Renais/irrigação sanguínea , Glomérulos Renais/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Estreptozocina
9.
Kidney Int ; 90(5): 950-964, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27325184

RESUMO

Autophagy is a highly regulated lysosomal protein degradation pathway that removes protein aggregates and damaged or excess organelles to maintain intracellular homeostasis and cell integrity. Dysregulation of autophagy is involved in the pathogenesis of a variety of metabolic and age-related diseases. Growing evidence suggests that autophagy is implicated in cell injury during renal diseases, both in the tubulointerstitial compartment and in glomeruli. Nevertheless, the impact of autophagy on renal disease progression and aging is still not fully understood. This review summarizes the recent advances in understanding the role of autophagy for kidney disease and aging.


Assuntos
Envelhecimento/fisiologia , Autofagia , Nefropatias/fisiopatologia , Animais
10.
J Am Soc Nephrol ; 27(12): 3545-3551, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27026367

RESUMO

Diabetic nephropathy (DN) is the leading cause of CKD in the Western world. Endothelin receptor antagonists have emerged as a novel treatment for DN, but the mechanisms underlying the protective effect remain unknown. We previously showed that both heparanase and endothelin-1 are essential for the development of DN. Here, we further investigated the role of these proteins in DN, and demonstrated that endothelin-1 activates podocytes to release heparanase. Furthermore, conditioned podocyte culture medium increased glomerular transendothelial albumin passage in a heparanase-dependent manner. In mice, podocyte-specific knockout of the endothelin receptor prevented the diabetes-induced increase in glomerular heparanase expression, consequent reduction in heparan sulfate expression and endothelial glycocalyx thickness, and development of proteinuria observed in wild-type counterparts. Our data suggest that in diabetes, endothelin-1 signaling, as occurs in endothelial activation, induces heparanase expression in the podocyte, damage to the glycocalyx, proteinuria, and renal failure. Thus, prevention of these effects may constitute the mechanism of action of endothelin receptor blockers in DN.


Assuntos
Endotelina-1/fisiologia , Glucuronidase/fisiologia , Glicocálix/enzimologia , Glomérulos Renais/enzimologia , Glomérulos Renais/ultraestrutura , Proteinúria/etiologia , Animais , Nefropatias Diabéticas/etiologia , Masculino , Camundongos , Podócitos/enzimologia
11.
J Am Soc Nephrol ; 27(1): 172-88, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25999406

RESUMO

Necrotizing and crescentic rapidly progressive GN (RPGN) is a life-threatening syndrome characterized by a rapid loss of renal function. Evidence suggests that podocyte expression of the transcription factor peroxisome proliferator-activated receptor γ (PPARγ) may prevent podocyte injury, but the function of glomerular PPARγ in acute, severe inflammatory GN is unknown. Here, we observed marked loss of PPARγ abundance and transcriptional activity in glomerular podocytes in experimental RPGN. Blunted expression of PPARγ in podocyte nuclei was also found in kidneys from patients diagnosed with crescentic GN. Podocyte-specific Pparγ gene targeting accentuated glomerular damage, with increased urinary loss of albumin and severe kidney failure. Furthermore, a PPARγ gain-of-function approach achieved by systemic administration of thiazolidinedione (TZD) failed to prevent severe RPGN in mice with podocyte-specific Pparγ gene deficiency. In nuclear factor erythroid 2-related factor 2 (NRF2)-deficient mice, loss of podocyte PPARγ was observed at baseline. NRF2 deficiency markedly aggravated the course of RPGN, an effect that was partially prevented by TZD administration. Furthermore, delayed administration of TZD, initiated after the onset of RPGN, still alleviated the severity of experimental RPGN. These findings establish a requirement for the NRF2-PPARγ cascade in podocytes, and we suggest that these transcription factors have a role in augmenting the tolerance of glomeruli to severe immune-complex mediated injury. The NRF2-PPARγ pathway may be a therapeutic target for RPGN.


Assuntos
Glomerulonefrite/etiologia , Fator 2 Relacionado a NF-E2/fisiologia , PPAR gama/biossíntese , Podócitos/metabolismo , Animais , Masculino , Camundongos
12.
Autophagy ; 11(7): 1130-45, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26039325

RESUMO

The glomerulus is a highly specialized capillary tuft, which under pressure filters large amounts of water and small solutes into the urinary space, while retaining albumin and large proteins. The glomerular filtration barrier (GFB) is a highly specialized filtration interface between blood and urine that is highly permeable to small and midsized solutes in plasma but relatively impermeable to macromolecules such as albumin. The integrity of the GFB is maintained by molecular interplay between its 3 layers: the glomerular endothelium, the glomerular basement membrane and podocytes, which are highly specialized postmitotic pericytes forming the outer part of the GFB. Abnormalities of glomerular ultrafiltration lead to the loss of proteins in urine and progressive renal insufficiency, underlining the importance of the GFB. Indeed, albuminuria is strongly predictive of the course of chronic nephropathies especially that of diabetic nephropathy (DN), a leading cause of renal insufficiency. We found that high glucose concentrations promote autophagy flux in podocyte cultures and that the abundance of LC3B II in podocytes is high in diabetic mice. Deletion of Atg5 specifically in podocytes resulted in accelerated diabetes-induced podocytopathy with a leaky GFB and glomerulosclerosis. Strikingly, genetic alteration of autophagy on the other side of the GFB involving the endothelial-specific deletion of Atg5 also resulted in capillary rarefaction and accelerated DN. Thus autophagy is a key protective mechanism on both cellular layers of the GFB suggesting autophagy as a promising new therapeutic strategy for DN.


Assuntos
Autofagia , Nefropatias Diabéticas/patologia , Nefropatias Diabéticas/prevenção & controle , Células Endoteliais/patologia , Podócitos/patologia , Animais , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Proteína 5 Relacionada à Autofagia , Células Cultivadas , Nefropatias Diabéticas/fisiopatologia , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/ultraestrutura , Deleção de Genes , Taxa de Filtração Glomerular/efeitos dos fármacos , Glucose/farmacologia , Integrases/metabolismo , Células Mesangiais/efeitos dos fármacos , Células Mesangiais/patologia , Células Mesangiais/ultraestrutura , Camundongos Endogâmicos C57BL , Proteínas Associadas aos Microtúbulos/deficiência , Proteínas Associadas aos Microtúbulos/metabolismo , Fenótipo , Podócitos/efeitos dos fármacos , Podócitos/ultraestrutura
13.
Semin Immunopathol ; 36(4): 479-90, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24948005

RESUMO

The recent years have seen a number of major progresses in the field of extracapillary glomerulonephritis. This entity is the final damage caused by unrelated immunological disorders such as immune complexes glomerular deposits or microvascular injury caused by proinflammatory cytokines, neutrophil extracellular traps (NET), and cell adhesion molecules in the context of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). This review provides a summary of recent advances in the understanding of crescentic glomerulonephritis, focusing on interplays of local immune cells and on local mediators participating to crescent formation especially in anti-glomerular basement membrane (anti-GBM) antibody disease. The recent advances about AAV and lupus nephritis are covered by other chapters of this issue. Nevertheless, these considerations may apply to the general case of crescentic glomerulonephritis of all causes.


Assuntos
Citocinas/imunologia , Glomerulonefrite/imunologia , Glomerulonefrite/patologia , Neutrófilos/imunologia , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/imunologia , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/patologia , Glomerulonefrite/classificação , Humanos , Neutrófilos/patologia
14.
J Am Soc Nephrol ; 25(5): 1050-62, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24722437

RESUMO

The endothelin system has emerged as a novel target for the treatment of diabetic nephropathy. Endothelin-1 promotes mesangial cell proliferation and sclerosis. However, no direct pathogenic effect of endothelin-1 on podocytes has been shown in vivo and endothelin-1 signaling in podocytes has not been investigated. This study investigated endothelin effects in podocytes during experimental diabetic nephropathy. Stimulation of primary mouse podocytes with endothelin-1 elicited rapid calcium transients mediated by endothelin type A receptors (ETARs) and endothelin type B receptors (ETBRs). We then generated mice with a podocyte-specific double deletion of ETAR and ETBR (NPHS2-Cre×Ednra(lox/lox)×Ednrb(lox/lox) [Pod-ETRKO]). In vitro, treatment with endothelin-1 increased total ß-catenin and phospho-NF-κB expression in wild-type glomeruli, but this effect was attenuated in Pod-ETRKO glomeruli. After streptozotocin injection to induce diabetes, wild-type mice developed mild diabetic nephropathy with microalbuminuria, mesangial matrix expansion, glomerular basement membrane thickening, and podocyte loss, whereas Pod-ETRKO mice presented less albuminuria and were completely protected from glomerulosclerosis and podocyte loss, even when uninephrectomized. Moreover, glomeruli from normal and diabetic Pod-ETRKO mice expressed substantially less total ß-catenin and phospho-NF-κB compared with glomeruli from counterpart wild-type mice. This evidence suggests that endothelin-1 drives development of glomerulosclerosis and podocyte loss through direct activation of endothelin receptors and NF-κB and ß-catenin pathways in podocytes. Notably, both the expression and function of the ETBR subtype were found to be important. Furthermore, these results indicate that activation of the endothelin-1 pathways selectively in podocytes mediates pathophysiologic crosstalk that influences mesangial architecture and sclerosis.


Assuntos
Nefropatias Diabéticas/etiologia , Endotelina-1/fisiologia , Podócitos/metabolismo , Podócitos/patologia , Animais , Nefropatias Diabéticas/genética , Nefropatias Diabéticas/patologia , Regulação para Baixo/genética , Regulação para Baixo/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , NF-kappa B/metabolismo , Receptor de Endotelina A/genética , Receptor de Endotelina A/metabolismo , Receptor de Endotelina B/genética , Receptor de Endotelina B/metabolismo , Transdução de Sinais/genética , Transdução de Sinais/fisiologia , beta Catenina/metabolismo
15.
Diabetes ; 60(11): 2861-71, 2011 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-21953612

RESUMO

OBJECTIVE: Class IIa histone deacetylases (HDACs) belong to a large family of enzymes involved in protein deacetylation and play a role in regulating gene expression and cell differentiation. Previously, we showed that HDAC inhibitors modify the timing and determination of pancreatic cell fate. The aim of this study was to determine the role of class IIa HDACs in pancreas development. RESEARCH DESIGN AND METHODS: We took a genetic approach and analyzed the pancreatic phenotype of mice lacking HDAC4, -5, and -9. We also developed a novel method of lentiviral infection of pancreatic explants and performed gain-of-function experiments. RESULTS: We show that class IIa HDAC4, -5, and -9 have an unexpected restricted expression in the endocrine ß- and δ-cells of the pancreas. Analyses of the pancreas of class IIa HDAC mutant mice revealed an increased pool of insulin-producing ß-cells in Hdac5(-/-) and Hdac9(-/-) mice and an increased pool of somatostatin-producing δ-cells in Hdac4(-/-) and Hdac5(-/-) mice. Conversely, HDAC4 and HDAC5 overexpression showed a decreased pool of insulin-producing ß-cells and somatostatin-producing δ-cells. Finally, treatment of pancreatic explants with the selective class IIa HDAC inhibitor MC1568 enhances expression of Pax4, a key factor required for proper ß-and δ-cell differentiation and amplifies endocrine ß- and δ-cells. CONCLUSIONS: We conclude that HDAC4, -5, and -9 are key regulators to control the pancreatic ß/δ-cell lineage. These results highlight the epigenetic mechanisms underlying the regulation of endocrine cell development and suggest new strategies for ß-cell differentiation-based therapies.


Assuntos
Histona Desacetilases/metabolismo , Células Secretoras de Insulina/metabolismo , Pâncreas/crescimento & desenvolvimento , Proteínas Repressoras/metabolismo , Células Secretoras de Somatostatina/metabolismo , Algoritmos , Animais , Animais Recém-Nascidos , Diferenciação Celular/efeitos dos fármacos , Embrião de Mamíferos/citologia , Embrião de Mamíferos/efeitos dos fármacos , Embrião de Mamíferos/metabolismo , Inibidores Enzimáticos/farmacologia , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Histona Desacetilases/química , Histona Desacetilases/genética , Proteínas de Homeodomínio/metabolismo , Insulina/metabolismo , Células Secretoras de Insulina/citologia , Células Secretoras de Insulina/efeitos dos fármacos , Isoenzimas/antagonistas & inibidores , Isoenzimas/genética , Isoenzimas/metabolismo , Camundongos , Camundongos Mutantes , Tamanho do Órgão , Especificidade de Órgãos , Fatores de Transcrição Box Pareados/metabolismo , Pâncreas/efeitos dos fármacos , Pâncreas/metabolismo , RNA Mensageiro/metabolismo , Proteínas Repressoras/antagonistas & inibidores , Proteínas Repressoras/genética , Somatostatina/metabolismo , Células Secretoras de Somatostatina/citologia , Células Secretoras de Somatostatina/efeitos dos fármacos , Técnicas de Cultura de Tecidos
16.
Cell Cycle ; 8(4): 536-44, 2009 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-19197155

RESUMO

Genes in the mammalian genome contain information necessary to build an organism during development. Epigenetic processes add a further degree of complexity. These mechanisms of temporal and spatial control of gene activity during the development of complex organisms modulate gene expression patterns without modifying the DNA sequence. Post-translational modifications of histones such as acetylation bestow the ability to modify genomic signals. Determining whether epigenetic changes are responsible for particular phenotypes is thus crucial to understand organ development. Here we review the role of histone deacetylase enzymes (HDACs) in guiding lineage commitment and driving cell differentiation, as well as their pharmacological manipulation using small-molecule HDAC inhibitors in various differentiation programs. In particular, we focus on the pancreas as we recently discovered that deacetylase inhibition favors generation of endocrine pancreatic cells. We also discuss the potential application of HDAC inhibitors for disease treatment, with particular emphasis on diabetes therapy.


Assuntos
Diferenciação Celular , Inibidores Enzimáticos/farmacologia , Inibidores de Histona Desacetilases , Animais , Encefalopatias/enzimologia , Encefalopatias/fisiopatologia , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/fisiologia , Linhagem da Célula , Células Endócrinas/citologia , Células Endócrinas/fisiologia , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/uso terapêutico , Histona Desacetilases/metabolismo , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/enzimologia , Pâncreas/citologia , Pâncreas/fisiologia
17.
Mol Cell Biol ; 28(20): 6373-83, 2008 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-18710955

RESUMO

During pancreas development, transcription factors play critical roles in exocrine and endocrine differentiation. Transcriptional regulation in eukaryotes occurs within chromatin and is influenced by posttranslational histone modifications (e.g., acetylation) involving histone deacetylases (HDACs). Here, we show that HDAC expression and activity are developmentally regulated in the embryonic rat pancreas. We discovered that pancreatic treatment with different HDAC inhibitors (HDACi) modified the timing and determination of pancreatic cell fate. HDACi modified the exocrine lineage via abolition and enhancement of acinar and ductal differentiation, respectively. Importantly, HDACi treatment promoted the NGN3 proendocrine lineage, leading to an increased pool of endocrine progenitors and modified endocrine subtype lineage choices. Interestingly, treatments with trichostatin A and sodium butyrate, two inhibitors of both class I and class II HDACs, enhanced the pool of beta cells. These results highlight the roles of HDACs at key points in exocrine and endocrine differentiation. They show the powerful use of HDACi to switch pancreatic cell determination and amplify specific cellular subtypes, with potential applications in cell replacement therapies in diabetes.


Assuntos
Linhagem da Célula/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Inibidores de Histona Desacetilases , Ilhotas Pancreáticas/citologia , Pâncreas/efeitos dos fármacos , Pâncreas/enzimologia , Células-Tronco/citologia , Animais , Apoptose/efeitos dos fármacos , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Feminino , Ácidos Hidroxâmicos/farmacologia , Ilhotas Pancreáticas/efeitos dos fármacos , Ilhotas Pancreáticas/enzimologia , Proteínas do Tecido Nervoso/metabolismo , Pâncreas/citologia , Pâncreas/embriologia , Pâncreas Exócrino/citologia , Pâncreas Exócrino/efeitos dos fármacos , Pâncreas Exócrino/enzimologia , Ductos Pancreáticos/citologia , Ductos Pancreáticos/efeitos dos fármacos , Ductos Pancreáticos/enzimologia , Células Secretoras de Polipeptídeo Pancreático/citologia , Células Secretoras de Polipeptídeo Pancreático/efeitos dos fármacos , Células Secretoras de Polipeptídeo Pancreático/enzimologia , Ratos , Ratos Wistar , Células-Tronco/efeitos dos fármacos , Ácido Valproico/farmacologia
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