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1.
Cells ; 10(2)2021 02 10.
Artigo em Inglês | MEDLINE | ID: mdl-33578631

RESUMO

Clinical manifestations of coronavirus disease 2019 (COVID-19) in pregnant women are diverse, and little is known of the impact of the disease on placental physiology. Severe acute respiratory syndrome coronavirus (SARS-CoV-2) has been detected in the human placenta, and its binding receptor ACE2 is present in a variety of placental cells, including endothelium. Here, we analyze the impact of COVID-19 in placental endothelium, studying by immunofluorescence the expression of von Willebrand factor (vWf), claudin-5, and vascular endothelial (VE) cadherin in the decidua and chorionic villi of placentas from women with mild and severe COVID-19 in comparison to healthy controls. Our results indicate that: (1) vWf expression increases in the endothelium of decidua and chorionic villi of placentas derived from women with COVID-19, being higher in severe cases; (2) Claudin-5 and VE-cadherin expression decrease in the decidua and chorionic villus of placentas from women with severe COVID-19 but not in those with mild disease. Placental histological analysis reveals thrombosis, infarcts, and vascular wall remodeling, confirming the deleterious effect of COVID-19 on placental vessels. Together, these results suggest that placentas from women with COVID-19 have a condition of leaky endothelium and thrombosis, which is sensitive to disease severity.


Assuntos
/complicações , Placenta/irrigação sanguínea , Placenta/patologia , Complicações Cardiovasculares na Gravidez/etiologia , Complicações Infecciosas na Gravidez/etiologia , Trombose/etiologia , Adulto , Antígenos CD/análise , /virologia , Caderinas/análise , Claudina-5/análise , Endotélio/irrigação sanguínea , Endotélio/patologia , Endotélio/virologia , Feminino , Humanos , Recém-Nascido , Microvasos/patologia , Microvasos/virologia , Gravidez , Complicações Cardiovasculares na Gravidez/patologia , Complicações Cardiovasculares na Gravidez/virologia , Complicações Infecciosas na Gravidez/patologia , Complicações Infecciosas na Gravidez/virologia , Trombose/patologia , Trombose/virologia , Adulto Jovem , Fator de von Willebrand/análise
2.
Viruses ; 13(2)2021 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-33499234

RESUMO

Respiratory viruses such as influenza and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are a constant threat to public health given their ability to cause global pandemics. Infection with either virus may lead to aberrant host responses, such as excessive immune cell recruitment and activation, dysregulated inflammation, and coagulopathy. These may contribute to the development of lung edema and respiratory failure. An increasing amount of evidence suggests that lung endothelial cells play a critical role in the pathogenesis of both viruses. In this review, we discuss how infection with influenza or SARS-CoV-2 may induce endothelial dysfunction. We compare the effects of infection of these two viruses, how they may contribute to pathogenesis, and discuss the implications for potential treatment. Understanding the differences between the effects of these two viruses on lung endothelial cells will provide important insight to guide the development of therapeutics.


Assuntos
Endotélio/virologia , Influenzavirus A/patogenicidade , Lesão Pulmonar/patologia , Lesão Pulmonar/virologia , /patogenicidade , Plaquetas/metabolismo , Citocinas/metabolismo , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Endotélio/metabolismo , Endotélio/patologia , Armadilhas Extracelulares/imunologia , Humanos , Junções Intercelulares/patologia , Lesão Pulmonar/terapia
3.
Nat Commun ; 12(1): 681, 2021 01 29.
Artigo em Inglês | MEDLINE | ID: mdl-33514719

RESUMO

Endothelial cells play a critical role in the adaptation of tissues to injury. Tissue ischemia induced by infarction leads to profound changes in endothelial cell functions and can induce transition to a mesenchymal state. Here we explore the kinetics and individual cellular responses of endothelial cells after myocardial infarction by using single cell RNA sequencing. This study demonstrates a time dependent switch in endothelial cell proliferation and inflammation associated with transient changes in metabolic gene signatures. Trajectory analysis reveals that the majority of endothelial cells 3 to 7 days after myocardial infarction acquire a transient state, characterized by mesenchymal gene expression, which returns to baseline 14 days after injury. Lineage tracing, using the Cdh5-CreERT2;mT/mG mice followed by single cell RNA sequencing, confirms the transient mesenchymal transition and reveals additional hypoxic and inflammatory signatures of endothelial cells during early and late states after injury. These data suggest that endothelial cells undergo a transient mes-enchymal activation concomitant with a metabolic adaptation within the first days after myocardial infarction but do not acquire a long-term mesenchymal fate. This mesenchymal activation may facilitate endothelial cell migration and clonal expansion to regenerate the vascular network.


Assuntos
Endotélio/patologia , Transição Epitelial-Mesenquimal/genética , Infarto do Miocárdio/patologia , Miocárdio/patologia , Animais , Movimento Celular/genética , Plasticidade Celular/genética , Proliferação de Células/genética , Células Cultivadas , Modelos Animais de Doenças , Células Endoteliais/patologia , Endotélio/citologia , Genes Reporter/genética , Células Endoteliais da Veia Umbilical Humana , Humanos , Proteínas Luminescentes/genética , Masculino , Camundongos , Camundongos Transgênicos , Miocárdio/citologia , RNA-Seq , Análise de Célula Única
4.
Front Immunol ; 11: 575047, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33123154

RESUMO

Reports suggest a role of endothelial dysfunction and loss of endothelial barrier function in COVID-19. It is well established that the endothelial glycocalyx-degrading enzyme heparanase contributes to vascular leakage and inflammation. Low molecular weight heparins (LMWH) serve as an inhibitor of heparanase. We hypothesize that heparanase contributes to the pathogenesis of COVID-19, and that heparanase may be inhibited by LMWH. To test this hypothesis, heparanase activity and heparan sulfate levels were measured in plasma of healthy controls (n = 10) and COVID-19 patients (n = 48). Plasma heparanase activity and heparan sulfate levels were significantly elevated in COVID-19 patients. Heparanase activity was associated with disease severity including the need for intensive care, lactate dehydrogenase levels, and creatinine levels. Use of prophylactic LMWH in non-ICU patients was associated with a reduced heparanase activity. Since there is no other clinically applied heparanase inhibitor currently available, therapeutic treatment of COVID-19 patients with low molecular weight heparins should be explored.


Assuntos
Endotélio/patologia , Glucuronidase/antagonistas & inibidores , Glucuronidase/sangue , Antagonistas de Heparina/uso terapêutico , Heparina de Baixo Peso Molecular/uso terapêutico , Junções Íntimas/patologia , Idoso , Betacoronavirus , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/patologia , Creatinina/sangue , Cuidados Críticos , Estudos Transversais , Feminino , Glucuronidase/metabolismo , Heparitina Sulfato/sangue , Humanos , Interleucina-6/sangue , L-Lactato Desidrogenase/sangue , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/imunologia , Pneumonia Viral/patologia
5.
Rev Soc Bras Med Trop ; 53: e20200472, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32965455

RESUMO

INTRODUCTION: In the genesis of coronavirus disease (COVID-19), there is a process of endotheliitis associated with thrombotic changes, no studies have reported the use of acetylsalicylic acid (ASA) as a possible therapeutic approach. Statins could potentiate the ASA therapy. METHODS: This is a series of 14 cases with a laboratory-confirmed diagnosis of COVID-19. All patients underwent the ASA therapy. Those who had risk factors for vascular disease also underwent the high-potency statin therapy. When symptoms were totally or practically resolved, patients were discharged and advised to continue medications for a complementary time, according to the clinical evolution of each patient. RESULTS: The mean age of monitored patients was 48.6 years. A total of 78.6% patients presented with at least one comorbidity, which could have contributed as a risk factor for a poor prognosis in the evolution of COVID-19. Four patients had secondary bacterial infections; three patients needed hospitalization. None of the cases progress to stage III, and all patients had remission of symptoms, with 100% survival. CONCLUSIONS: the process of endothelial dysfunction in COVID-19 involves disseminated thrombosis, initially microvascular and later expansion into larger vessels. ASA could act as a secondary prophylaxis and prevent thrombosis from developing and reaching stage III of the disease. As this was a case series, we cannot provide definitive conclusions; however, this study allows us to formulate hypotheses and support clinical trials to evaluate benefits of the ASA therapy in the treatment of COVID-19.


Assuntos
Aspirina/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Inflamação/tratamento farmacológico , Isquemia/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Trombose/tratamento farmacológico , Betacoronavirus , Comorbidade , Endotélio/efeitos dos fármacos , Endotélio/patologia , Humanos , Pessoa de Meia-Idade , Pandemias
6.
Inflamm Res ; 69(12): 1235-1244, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32909096

RESUMO

OBJECTIVE: The inflammatory response and the presence of macrophages are reported to be necessary for proper muscle regeneration. However, our understanding of the molecular mechanisms governing how macrophages signal to promote muscle regeneration is incomplete. METHODS AND RESULTS: Here we conditionally deleted Wls, which is required for Wnt secretion, from macrophages and examined the impact on endothelial permeability following muscle injury. The expression of Wnt ligands and Wls was increased in the tibialis anterior (TA) of mice 2 days following BaCl2 injury. Loss of macrophage Wls inhibited the loss of endothelial barrier function, as measured by transendothelial resistance and Evans blue dye permeability assays. Interestingly, the blockade in endothelial permeability correlated with reduced VEGF levels and pretreatment of wild type endothelial cells with a VEGFR2 blocking antibody was sufficient to reduce endothelial permeability induced by stimulated macrophage supernatant. We also found that macrophage Wls-null TAs had myocytes with reduced cross-sectional area 7 day post-injury suggesting a delay in muscle regeneration. CONCLUSION: Our results indicate that macrophage-derived Wnt signaling increases endothelial permeability in a VEGF-dependent fashion following muscle injury. Our findings implicate macrophages as a primary source of Wnt ligands following muscle injury and highlight the Wnt pathway as a therapeutic target following injury.


Assuntos
Endotélio/patologia , Macrófagos/patologia , Músculo Esquelético/lesões , Músculo Esquelético/patologia , Via de Sinalização Wnt , Animais , Anticorpos Bloqueadores/farmacologia , Células Cultivadas , Células Endoteliais/patologia , Humanos , Camundongos , Camundongos Knockout , Permeabilidade , Regeneração , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Cicatrização
7.
Inflamm Res ; 69(8): 745-756, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32488318

RESUMO

BACKGROUND: SARS-Cov-2 is a single-stranded RNA virus, a Betacoronavirus, composed of 16 non-structural proteins, with specific roles in replication of coronaviruses. The pathogenesis of COVID-19 is not yet fully understood. The virus and host factors interplay among distinct outcomes of infected patients. METHODS: Using MeSH (Medical Subject Headings) in PubMed, authors searched for articles cotaining information on COVID-19 and the skin. RESULTS: The pathophysiology of the disease is multifactorial: association with innate immune response, hypercoagulability state, lung tissue damage, neurological and/or gastrointestinal tract involvement, monocytic/macrophage activation syndrome, culminating in exaggerated cytokine secretion, called "cytokine storm", which leads to worsening and death. These systemic conditions may be associated with cutaneous lesions, that have polymorphic aspects, where at histopathological level show involvement in different skin changes. These lesions may be associated with multisystemic manifestations that could occur due to angiotensin-converting enzyme 2 receptor and transmembrane serine protease action, allowing the pulmonary infection and possibly skin manifestation. Several reports in literature show cutaneous lesions similar to chilblain, urticarial eruptions, diffuse or disseminated erythema, livedo racemosa, blue toe syndrome, retiform purpura, vesicle trunk, purpuric exanthema or exanthema with clinical aspects of symmetrical drug-related intertriginous and flexural exanthema (SDRIFE) and others. CONCLUSIONS: This review describes the complexity of Covid-19, pathophysiological and clinical aspects, dermatological finding and other dermatological conditions associated with SARS-CoV-2 infection or COVID-19.


Assuntos
Infecções por Coronavirus/complicações , Infecções por Coronavirus/fisiopatologia , Pneumonia Viral/complicações , Pneumonia Viral/fisiopatologia , Dermatopatias/complicações , Dermatopatias/fisiopatologia , Arteríolas/patologia , Betacoronavirus , Capilares/patologia , Síndrome da Liberação de Citocina/virologia , Endotélio/patologia , Endotélio/virologia , Humanos , Sistema Imunitário , Pulmão/patologia , Pulmão/virologia , Pandemias , Peptidil Dipeptidase A/metabolismo , Dermatopatias/virologia , Resultado do Tratamento
8.
PLoS One ; 15(5): e0233469, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32433661

RESUMO

We assessed the association between metabolic health and markers of inflammation and of endothelial dysfunction using data from the Ewha Birth and Growth Cohort Study. The data of 195 subjects aged 13-15 years were analyzed. To assess metabolic syndrome, continuous metabolic syndrome (cMets) scores were calculated. We measured the levels of high-sensitivity C-reactive protein (hs-CRP), intercellular adhesion molecule 1 (ICAM-1), and vascular cell adhesion molecule 1 (VCAM-1) as markers of inflammation and endothelial dysfunction. An increase of one SD in the cMets score resulted in a 1.25-fold (95% CI 1.10-1.42) increase in the risk of acute inflammatory status and a 1.26-fold (95% CI 1.11-1.43) increase in the risk of endothelial dysfunction as defined by ICAM-1, while VCAM-1 showed a meaningless trend. Of the metabolic components, body mass index (BMI) was positively associated with elevated hs-CRP levels and high-density lipoprotein cholesterol (HDL-c) levels were negatively associated with elevated ICAM-1 levels. Additionally, a mediation analysis showed that a high BMI was directly related to elevated hs-CRP levels and indirectly related to elevated ICAM-1 levels via HDL-c. Our findings show that poor metabolic health was related to an unfavorable inflammatory status and endothelial dysfunction in adolescents.


Assuntos
Endotélio/patologia , Inflamação/diagnóstico , Adolescente , Biomarcadores/análise , Índice de Massa Corporal , Proteína C-Reativa/análise , HDL-Colesterol/sangue , Endotélio/metabolismo , Humanos , Inflamação/sangue , Inflamação/metabolismo , Inflamação/patologia , Molécula 1 de Adesão Intercelular/sangue , Síndrome Metabólica/sangue , Síndrome Metabólica/diagnóstico , Molécula 1 de Adesão de Célula Vascular/sangue
9.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 36(2): 175-179, 2020 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-32314716

RESUMO

Diabetic nephropathy (DN) is the most common cause of global end-stage renal disease (ESRD) and is one of the leading causes of mortality in patients with type 1 and type 2 diabetes. Recent studies have found that autoimmunity is closely related to the occurrence and development of DN, especially the autoantibodies which play a crucial role in the pathogenesis of DN. Currently, autoantibodies found in the serum of DN patients mainly include G-protein coupled receptor autoantibodies, pancreatic autoantibodies and autoantibodies related to endothelial cell damage. In the special environment of diabetes, high glucose (HG) can stimulate the production of a variety of autoantibodies, which can mediate the damage of renal function via different mechanisms and affect the progression of DN. Therefore, it is important to explore the role of autoantibodies in the pathogenesis of DN.


Assuntos
Autoanticorpos/imunologia , Diabetes Mellitus Tipo 2/complicações , Nefropatias Diabéticas/imunologia , Progressão da Doença , Endotélio/patologia , Humanos
11.
Metabolism ; 107: 154226, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32277945

RESUMO

BACKGROUND: Aberrant endothelial function is a major contributing factor in cardiovascular disease. Dyslipidemia leads to decreased nitric oxide (NO) bioavailability, an early sign of endothelial failure. Low insulin gene enhancer protein (ISL1) levels decrease healthy NO bioavailability. We hypothesized that the microRNA miR-652-3p negatively regulates endothelial ISL1 expression and that dyslipidemia-induced miR-652-3p upregulation induces aberrant endothelial functioning via ISL1 downregulation. METHODS: Various in vitro experiments were conducted in human umbilical vein endothelial cells (HUVECs). Luciferase assays were performed in HEK293 cells. We constructed a high-fat diet (HFD) Apoe-/- murine model of dyslipidemia and a rat model of low-density lipoprotein (LDL)-induced dyslipidemia to conduct in vivo and ex vivo experiments. RESULTS: Luciferase assays confirmed miR-652-3p's targeting of the ISL1 3'-untranslated region (3'-UTR). Simvastatin blocked oxidized LDL (ox-LDL)-induced increases in miR-652-3p and ox-LDL-induced decreases in ISL1 protein expression, endothelial NO synthase (eNOS) activation, and NO production. Simvastatin's effects were abrogated by miR-652-3p overexpression and phenocopied by miR-652-3p inhibition. The dyslipidemic mouse model exhibited increased miR-652-3p and decreased ISL1 protein levels in the endothelium, effects opposed by simvastatin or miR-652-3p inhibition. The impact of simvastatin in vivo was abolished by overexpressing miR-652-3p or knocking-down ISL1. The rat model of dyslipidemia exhibited a similar pattern of miR-652-3p upregulation, attenuated ISL1 protein levels, decreased eNOS activation, and decreased NO production, effects mitigated by simvastatin. CONCLUSIONS: Dyslipidemia upregulates endothelial miR-652-3p, which decreases ISL1 protein levels, eNOS activation, and NO production. Simvastatin therapy lowers endothelial miR-652-3p expression to protect endothelial function under dyslipidemic conditions.


Assuntos
Dislipidemias/patologia , Dislipidemias/prevenção & controle , Endotélio/patologia , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Proteínas com Homeodomínio LIM/biossíntese , MicroRNAs/biossíntese , Fatores de Transcrição/biossíntese , Animais , Apolipoproteínas E/genética , Regulação para Baixo/efeitos dos fármacos , Dislipidemias/genética , Ativação Enzimática , Regulação da Expressão Gênica/efeitos dos fármacos , Células HEK293 , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , MicroRNAs/efeitos dos fármacos , Óxido Nítrico/biossíntese , Óxido Nítrico Sintase Tipo III/metabolismo , Ratos , Ratos Sprague-Dawley
12.
Biochim Biophys Acta Mol Basis Dis ; 1866(6): 165763, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32169502

RESUMO

Excess circulating fatty acids contribute to endothelial dysfunction that subsequently aggravates the metabolic conditions such as fatty liver diseases. However, the exact mechanism of this event is not fully understood, and the investigation on the effect of a direct exposure to fatty acids together with their subsequent fate is of interest. In this work we employed a chemically specific and label-free techniques such as Raman and CARS microscopies, to investigate the process of lipid droplets (LDs) formation in endothelial cells and hepatocytes after exposure to oleic and palmitic acid. We aimed to observe the changes in the composition of LDs associated with metabolism and degradation of lipids. We were able to characterize the diversity in the formation of LDs in endothelium as compared to hepatocytes, as well as the differences in the formation of LDs and degradation manner with respect to the used fatty acid. Thus, for the first time the spectral characteristics of LDs formed in endothelial cells after incubation with oleic and palmitic acid is presented, including the time-dependent changes in their chemical composition.


Assuntos
Hepatócitos/metabolismo , Gotículas Lipídicas/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/metabolismo , Linhagem Celular , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Endotélio/efeitos dos fármacos , Endotélio/metabolismo , Endotélio/patologia , Ácidos Graxos/metabolismo , Ácidos Graxos/farmacologia , Hepatócitos/efeitos dos fármacos , Humanos , Gotículas Lipídicas/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/patologia , Ácido Oleico/farmacologia , Ácido Palmítico/metabolismo , Ácido Palmítico/farmacologia , Análise Espectral Raman
13.
Sci Rep ; 10(1): 3054, 2020 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-32080247

RESUMO

Brain injuries caused by an explosive blast or blunt force is typically presumed to associate with mechanical trauma to the brain tissue. Recent findings from our laboratory suggest that shockwaves produced by a blast can generate micron-sized bubbles in the tissue. The collapse of microbubbles (i.e., microcavitation) may induce a mechanical trauma and compromise the integrity of the blood-brain endothelium (BBE). To test our hypothesis, we engineered a BBE model to determine the effect of microbubbles on the structural and functional changes in the BBE. Using monolayers of mouse primary brain microvascular endothelial cells, the permeability coefficient was measured following simulated blast-induced microcavitation. This event down-regulated the expression of tight junction markers, disorganized the cell-cell junction, and increased permeability. Since poloxamers have been shown to rescue damaged cells, the cells were treated with the FDA-approved poloxamer 188 (P188). The results indicate P188 recovered the permeability, restored the tight junctions, and suppressed the expressions of matrix metalloproteinases. The biomimetic interface we developed appears to provide a systematic approach to replicate the structure and function of BBE, determine its alteration in response to traumatic brain injury, and test potential therapeutic treatments to repair the damaged brain endothelium.


Assuntos
Lesões Encefálicas Traumáticas/patologia , Encéfalo/patologia , Endotélio/patologia , Poloxâmero/farmacologia , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Encéfalo/irrigação sanguínea , Adesão Celular/efeitos dos fármacos , Permeabilidade da Membrana Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Endocitose/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Inflamação/patologia , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Superóxidos/metabolismo
14.
FASEB J ; 34(1): 95-106, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31914697

RESUMO

Diabetic nephropathy (DN) is one of the leading causes of mortality in diabetic patients, but its pathogenesis is unclear. We aimed to study the role of the pro-ANP convertase Corin in the pathogenesis of DN. Corin and ANP expression in DN rat kidneys and high-glucose-treated HK-2 cells was analyzed by real-time PCR, western blotting, and immunohistochemical staining. The effect of Corin-siRNA or ANP-siRNA HK-2 cells on EA.hy926 cell migration was determined by scratch-wound healing assay. The expression of mitogen-activated protein kinase (MAPK) and endothelial NO synthase (eNOS) in EA.hy926 cells treated with conditioned medium from Corin-siRNA- or ANP-siRNA-transfected HK-2 cells was determined by western blotting. We found a significant reduction in Corin and ANP expression in DN rat kidneys. These results were recapitulated in HK-2 cells treated with high glucose. EA.hy926 cells treated with conditioned medium from Corin-deficient HK-2 cells had inhibited migration, increased MAPK activity, and decreased eNOS activity. Similar effects were observed with ANP-siRNA transfection. Finally, adding ANP to the Corin-deficient HK-2 conditioned medium rescued the above defects, indicating that Corin mediates its effects through ANP. In conclusion, Corin plays a renoprotective role through pro-ANP processing, and defects in Corin cause endothelial dysfunction through MAPK and eNOS signaling in DN.


Assuntos
Nefropatias Diabéticas/metabolismo , Endotélio/patologia , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Serina Endopeptidases/metabolismo , Animais , Linhagem Celular , Proliferação de Células , Sobrevivência Celular , Diabetes Mellitus Experimental , Endotélio/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Glucose/toxicidade , Células Endoteliais da Veia Umbilical Humana , Humanos , Túbulos Renais Proximais/citologia , Masculino , Camundongos , Quinases de Proteína Quinase Ativadas por Mitógeno/genética , Óxido Nítrico Sintase Tipo III/genética , Interferência de RNA , RNA Interferente Pequeno , Ratos Sprague-Dawley , Serina Endopeptidases/genética , Serina Endopeptidases/urina
15.
Cell Prolif ; 53(3): e12763, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31925859

RESUMO

In recent years, although the development of clinical therapy for diabetic kidney disease (DKD) has made great progress, the progression of DKD still cannot be controlled. Therefore, further study of the pathogenesis of DKD and improvements in DKD treatment are crucial for prognosis. Traditional studies have shown that podocyte injury plays an important role in this process. Recently, it has been found that glomerulotubular balance and tubuloglomerular feedback (TGF) may be involved in the progression of DKD. Glomerulotubular balance is the specific gravity absorption of the glomerular ultrafiltrate by the proximal tubules, which absorbs only 65% to 70% of the ultrafiltrate. This ensures that the urine volume will not change much regardless of whether the glomerular filtration rate (GFR) increases or decreases. TGF is one of the significant mechanisms of renal blood flow and self-regulation of GFR, but how they participate in the development of DKD in the pathological state and the specific mechanism is not clear. Injury to tubular epithelial cells (TECs) is the key link in DKD. Additionally, injury to glomerular endothelial cells (GECs) plays a key role in the early occurrence and development of DKD. However, TECs and GECs are close to each other in anatomical position and can crosstalk with each other, which may affect the development of DKD. Therefore, the purpose of this review was to summarize the current knowledge on the crosstalk between TECs and GECs in the pathogenesis of DKD and to highlight specific clinical and potential therapeutic strategies.


Assuntos
Nefropatias Diabéticas/fisiopatologia , Glomérulos Renais/fisiopatologia , Túbulos Renais/fisiopatologia , Animais , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/patologia , Progressão da Doença , Endotélio/citologia , Endotélio/metabolismo , Endotélio/patologia , Humanos , Glomérulos Renais/citologia , Glomérulos Renais/metabolismo , Glomérulos Renais/patologia , Túbulos Renais/citologia , Túbulos Renais/metabolismo , Túbulos Renais/patologia , Urotélio/citologia , Urotélio/metabolismo , Urotélio/patologia , Urotélio/fisiopatologia
16.
Nat Commun ; 11(1): 214, 2020 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-31924781

RESUMO

Neutrophils are implicated in the pathogenesis of atherosclerosis but are seldom detected in atherosclerotic plaques. We investigated whether neutrophil-derived microvesicles may influence arterial pathophysiology. Here we report that levels of circulating neutrophil microvesicles are enhanced by exposure to a high fat diet, a known risk factor for atherosclerosis. Neutrophil microvesicles accumulate at disease-prone regions of arteries exposed to disturbed flow patterns, and promote vascular inflammation and atherosclerosis in a murine model. Using cultured endothelial cells exposed to disturbed flow, we demonstrate that neutrophil microvesicles promote inflammatory gene expression by delivering miR-155, enhancing NF-κB activation. Similarly, neutrophil microvesicles increase miR-155 and enhance NF-κB at disease-prone sites of disturbed flow in vivo. Enhancement of atherosclerotic plaque formation and increase in macrophage content by neutrophil microvesicles is dependent on miR-155. We conclude that neutrophils contribute to vascular inflammation and atherogenesis through delivery of microvesicles carrying miR-155 to disease-prone regions.


Assuntos
Aterosclerose/metabolismo , Endotélio/metabolismo , MicroRNAs/metabolismo , Neutrófilos/metabolismo , Animais , Aterosclerose/patologia , Dieta Hiperlipídica , Modelos Animais de Doenças , Células Endoteliais , Endotélio/patologia , Regulação da Expressão Gênica , Humanos , Macrófagos/metabolismo , Camundongos , Camundongos Knockout para ApoE , MicroRNAs/genética , NF-kappa B/metabolismo , Placa Aterosclerótica/metabolismo , Placa Aterosclerótica/patologia
17.
J Photochem Photobiol B ; 204: 111764, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31972451

RESUMO

This study was to assess the impact on the cornea and eye blink activity of adapting rabbits to continuous lighting (CL) compared to a 14:10 light:dark cycle. Female New Zealand White rabbits (2 to 2.5 kg) were maintained under a light: dark (L:D) cycle or switched to continuous fluorescent lighting (CL) for an average of 17 +/- 2 days. Animal behaviour in their cages was manually recorded using an event marker and in vivo slitlamp biomicroscopy at 40× undertaken in mid-afternoon. Animals were then euthanized and the corneas prepared for scanning electron microscopy (SEM). From images taken at 500× from the central region of the corneas, the number of exfoliating (desquamating) cells and the relative number of different cells with light, medium or dark reflexes were assessed for the corneal epithelial surface, while the number of cells/unit area were assessed for both corneal epithelium and endothelium. Exposure to continuous lighting was associated with higher number of eye blink events (15.7 vs 8.2/15 min) and mild corneal surface alterations evident by biomicroscopy with higher numbers of intra-epithelial 'granules' (32 +/- 14 vs. 4 +/- 3/sq. mm). SEM revealed low numbers of exfoliating cells on the corneal epithelial surface in all CL-adapted animals, but not in L:D controls. Trends were observed for there to be slightly higher numbers of epithelial cells/unit area, higher numbers of small light reflex cells and lower numbers of larger dark reflex cells in CL animals. The corneal endothelium showed no obvious adverse effects in CL-adapted animals but the percentage of 'hexagonal' cells was slightly higher compared to L:D controls. The results indicate that even a short period of exposure of laboratory-raised rabbits to constant lighting can be associated with mild adverse effects on the corneal epithelial surface.


Assuntos
Epitélio Anterior/efeitos da radiação , Iluminação , Animais , Piscadela/efeitos da radiação , Contagem de Células , Endotélio/citologia , Endotélio/patologia , Endotélio/efeitos da radiação , Epitélio Anterior/citologia , Epitélio Anterior/patologia , Feminino , Microscopia Eletrônica de Varredura , Coelhos
18.
J Neurosci ; 40(9): 1943-1955, 2020 02 26.
Artigo em Inglês | MEDLINE | ID: mdl-31974206

RESUMO

Currently, the role of transient receptor potential vanilloid type 4 (TRPV4), a nonselective cation channel in the pathology of spinal cord injury (SCI), is not recognized. Herein, we report the expression and contribution of TRPV4 in the pathology of scarring and endothelial and secondary damage after SCI. TRPV4 expression increased during the inflammatory phase in female rats after SCI and was expressed primarily by cells at endothelial-microglial junctions. Two-photon microscopy of intracellular-free Ca2+ levels revealed a biphasic increase at similar time points after SCI. Expression of TRPV4 at the injury epicenter, but not intracellular-free Ca2+, progressively increases with the severity of the injury. Activation of TRPV4 with specific agonist altered the organization of endothelial cells, affected tight junctions in the hCMEC/D3 BBB cell line in vitro, and increases the scarring in rat spinal cord as well as induced endothelial damage. By contrast, suppression of TRPV4 with a specific antagonist or in female Trpv4 KO mouse attenuated inflammatory cytokines and chemokines, prevented the degradation of tight junction proteins, and preserve blood-spinal cord barrier integrity, thereby attenuate the scarring after SCI. Likewise, secondary damage was reduced, and behavioral outcomes were improved in Trpv4 KO mice after SCI. These results suggest that increased TRPV4 expression disrupts endothelial cell organization during the early inflammatory phase of SCI, resulting in tissue damage, vascular destabilization, blood-spinal cord barrier breakdown, and scarring. Thus, TRPV4 inhibition/knockdown represents a promising therapeutic strategy to stabilize/protect endothelial cells, attenuate nociception and secondary damage, and reduce scarring after SCI.SIGNIFICANCE STATEMENT TRPV4, a calcium-permeable nonselective cation channel, is widely expressed in both excitable and nonexcitable cells. Spinal cord injury (SCI) majorly caused by trauma/accidents is associated with changes in osmolarity, mechanical injury, and shear stress. After SCI, TRPV4 was increased and were found to be linked with the severity of injury at the epicenter at the time points that were reported to be critical for repair/treatment. Activation of TRPV4 was damaging to endothelial cells that form the blood-spinal cord barrier and thus contributes to scarring (glial and fibrotic). Importantly, inhibition/knockdown of TRPV4 prevented these effects. Thus, the manipulation of TRPV4 signaling might lead to new therapeutic strategies or combinatorial therapies to protect endothelial cells and enhance repair after SCI.


Assuntos
Endotélio/patologia , Traumatismos da Medula Espinal/metabolismo , Traumatismos da Medula Espinal/patologia , Medula Espinal/patologia , Canais de Cátion TRPV/metabolismo , Animais , Comportamento Animal , Quimiocinas/metabolismo , Citocinas/metabolismo , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Feminino , Locomoção , Camundongos , Camundongos Knockout , Microglia/metabolismo , Microglia/patologia , Ratos , Ratos Sprague-Dawley , Traumatismos da Medula Espinal/psicologia , Canais de Cátion TRPV/genética , Junções Íntimas/metabolismo , Junções Íntimas/patologia
19.
Proc Natl Acad Sci U S A ; 117(3): 1753-1761, 2020 01 21.
Artigo em Inglês | MEDLINE | ID: mdl-31896584

RESUMO

Carbon dioxide (CO2), the major product of metabolism, has a strong impact on cerebral blood vessels, a phenomenon known as cerebrovascular reactivity. Several vascular risk factors such as hypertension or diabetes dampen this response, making cerebrovascular reactivity a useful diagnostic marker for incipient vascular pathology, but its functional relevance, if any, is still unclear. Here, we found that GPR4, an endothelial H+ receptor, and endothelial Gαq/11 proteins mediate the CO2/H+ effect on cerebrovascular reactivity in mice. CO2/H+ leads to constriction of vessels in the brainstem area that controls respiration. The consequential washout of CO2, if cerebrovascular reactivity is impaired, reduces respiration. In contrast, CO2 dilates vessels in other brain areas such as the amygdala. Hence, an impaired cerebrovascular reactivity amplifies the CO2 effect on anxiety. Even at atmospheric CO2 concentrations, impaired cerebrovascular reactivity caused longer apneic episodes and more anxiety, indicating that cerebrovascular reactivity is essential for normal brain function. The site-specific reactivity of vessels to CO2 is reflected by regional differences in their gene expression and the release of vasoactive factors from endothelial cells. Our data suggest the central nervous system (CNS) endothelium as a target to treat respiratory and affective disorders associated with vascular diseases.


Assuntos
Ansiedade/metabolismo , Sistema Cardiovascular/metabolismo , Endotélio/metabolismo , Transtornos Respiratórios/metabolismo , Tonsila do Cerebelo , Animais , Arteríolas/patologia , Encéfalo/fisiologia , Tronco Encefálico/metabolismo , Dióxido de Carbono/metabolismo , Sistema Nervoso Central/metabolismo , Modelos Animais de Doenças , Endotélio/patologia , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/genética , Subunidades alfa Gq-G11 de Proteínas de Ligação ao GTP/metabolismo , Expressão Gênica , Humanos , Hipercapnia/metabolismo , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Receptores Acoplados a Proteínas-G/genética , Receptores Acoplados a Proteínas-G/metabolismo , Respiração , Fatores de Risco , Transdução de Sinais
20.
Clin Exp Immunol ; 199(1): 97-108, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31509227

RESUMO

Kidney injury significantly increases overall mortality. Neutrophilic granulocytes (neutrophils) are the most abundant human blood leukocytes. They are characterized by a high turnover rate, chiefly controlled by granulocyte colony stimulating factor (G-CSF). The role of kidney injury and uremia in regulation of granulopoiesis has not been reported. Kidney transplantation, which inherently causes ischemia-reperfusion injury of the graft, elevated human neutrophil expression of the surface glycoprotein CD177. CD177 is among the most G-CSF-responsive neutrophil genes and reversibly increased on neutrophils of healthy donors who received recombinant G-CSF. In kidney graft recipients, a transient rise in neutrophil CD177 correlated with renal tubular epithelial G-CSF expression. In contrast, CD177 was unaltered in patients with chronic renal impairment and independent of renal replacement therapy. Under controlled conditions of experimental ischemia-reperfusion and unilateral ureteral obstruction injuries in mice, renal G-CSF mRNA and protein expression significantly increased and systemic neutrophilia developed. Human renal tubular epithelial cell G-CSF expression was promoted by hypoxia and proinflammatory cytokine interleukin 17A in vitro. Clinically, recipients of ABO blood group-incompatible kidney grafts developed a larger rise in neutrophil CD177. Their grafts are characterized by complement C4d deposition on the renal endothelium, even in the absence of rejection. Indeed, complement activation, but not hypoxia, induced primary human endothelial cell G-CSF expression. Our data demonstrate that kidney injury induces renal G-CSF expression and modulates granulopoiesis. They delineate differential G-CSF regulation in renal epithelium and endothelium. Altered granulopoiesis may contribute to the systemic impact of kidney injury.


Assuntos
Basigina/metabolismo , Endotélio/metabolismo , Regulação da Expressão Gênica , Fator Estimulador de Colônias de Granulócitos/biossíntese , Neutrófilos/metabolismo , Insuficiência Renal/metabolismo , Trombopoese , Animais , Basigina/imunologia , Modelos Animais de Doenças , Endotélio/imunologia , Endotélio/patologia , Feminino , Fator Estimulador de Colônias de Granulócitos/imunologia , Humanos , Transplante de Rim , Masculino , Camundongos , Neutrófilos/imunologia , Neutrófilos/patologia , Insuficiência Renal/imunologia , Insuficiência Renal/patologia , Insuficiência Renal/cirurgia , Traumatismo por Reperfusão/imunologia , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia , Obstrução Ureteral/imunologia , Obstrução Ureteral/metabolismo , Obstrução Ureteral/patologia
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