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1.
Biomolecules ; 11(6)2021 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-34207942

RESUMO

Blood pressure (BP) follows a circadian rhythm, it increases on waking in the morning and decreases during sleeping at night. Disruption of the circadian BP rhythm has been reported to be associated with worsened cardiovascular and renal outcomes, however the underlying molecular mechanisms are still not clear. In this review, we briefly summarized the current understanding of the circadian BP regulation and provided therapeutic overview of the relationship between circadian BP rhythm and cardiovascular and renal health and disease.


Assuntos
Pressão Sanguínea/fisiologia , Doenças Cardiovasculares/fisiopatologia , Ritmo Circadiano/fisiologia , Nefropatias/fisiopatologia , Doenças Cardiovasculares/metabolismo , Sistema Cardiovascular/fisiopatologia , China , Humanos , Hipertensão/fisiopatologia , Rim/fisiopatologia , Nefropatias/metabolismo
2.
FASEB J ; 35(5): e21530, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33813752

RESUMO

Circadian clock is involved in regulating most renal physiological functions, including water and electrolyte balance and blood pressure homeostasis, however, the role of circadian clock in renal pathophysiology remains largely unknown. Here we aimed to investigate the role of Bmal1, a core clock component, in the development of renal fibrosis, the hallmark of pathological features in many renal diseases. The inducible Bmal1 knockout mice (iKO) whose gene deletion occurred in adulthood were used in the study. Analysis of the urinary water, sodium and potassium excretion showed that the iKO mice exhibit abolished diurnal variations. In the model of renal fibrosis induced by unilateral ureteral obstruction, the iKO mice displayed significantly decreased tubulointerstitial fibrosis reflected by attenuated collagen deposition and mitigated expression of fibrotic markers α-SMA and fibronectin. The hedgehog pathway transcriptional effectors Gli1 and Gli2, which have been reported to be involved in the pathogenesis of renal fibrosis, were significantly decreased in the iKO mice. Mechanistically, ChIP assay and luciferase reporter assay revealed that BMAL1 bound to the promoter of and activate the transcription of Gli2, but not Gli1, suggesting that the involvement of Bmal1 in renal fibrosis was possibly mediated via Gli2-dependent mechanisms. Furthermore, treatment with TGF-ß increased Bmal1 in cultured murine proximal tubular cells. Knockdown of Bmal1 abolished, while overexpression of Bmal1 increased, Gli2 and the expression of fibrosis-related genes. Collectively, these results revealed a prominent role of the core clock gene Bmal1 in tubulointerstitial fibrosis. Moreover, we identified Gli2 as a novel target of Bmal1, which may mediate the adverse effect of Bmal1 in obstructive nephropathy.


Assuntos
Fatores de Transcrição ARNTL/fisiologia , Fibrose/prevenção & controle , Regulação da Expressão Gênica , Nefropatias/prevenção & controle , Proteínas Circadianas Period/fisiologia , Proteína Gli2 com Dedos de Zinco/antagonistas & inibidores , Animais , Animais Recém-Nascidos , Fibrose/etiologia , Fibrose/metabolismo , Fibrose/patologia , Nefropatias/etiologia , Nefropatias/metabolismo , Nefropatias/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína Gli2 com Dedos de Zinco/genética , Proteína Gli2 com Dedos de Zinco/metabolismo
3.
J Pharmacol Exp Ther ; 375(1): 40-48, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32759273

RESUMO

Deletion of microsomal prostaglandin E2 synthase-1 (mPGES-1) inhibits inflammation and protects against atherosclerotic vascular diseases but displayed variable influence on pathologic cardiac remodeling. Overactivation of ß-adrenergic receptors (ß-ARs) causes heart dysfunction and cardiac remodeling, whereas the role of mPGES-1 in ß-AR-induced cardiac remodeling is unknown. Here we addressed this question using mPGES-1 knockout mice, subjecting them to isoproterenol, a synthetic nonselective agonist for ß-ARs, at 5 or 15 mg/kg per day to induce different degrees of cardiac remodeling in vivo. Cardiac structure and function were assessed by echocardiography 24 hours after the last of seven consecutive daily injections of isoproterenol, and cardiac fibrosis was examined by Masson trichrome stain in morphology and by real-time polymerase chain reaction for the expression of fibrosis-related genes. The results showed that deletion of mPGES-1 had no significant effect on isoproterenol-induced cardiac dysfunction or hypertrophy. However, the cardiac fibrosis was dramatically attenuated in the mPGES-1 knockout mice after either low-dose or high-dose isoproterenol exposure. Furthermore, in vitro study revealed that overexpression of mPGES-1 in cultured cardiac fibroblasts increased isoproterenol-induced fibrosis, whereas knocking down mPGES-1 in cardiac myocytes decreased the fibrogenesis of fibroblasts. In conclusion, mPGES-1 deletion protects against isoproterenol-induced cardiac fibrosis in mice, and targeting mPGES-1 may represent a novel strategy to attenuate pathologic cardiac fibrosis, induced by ß-AR agonists. SIGNIFICANCE STATEMENT: Inhibitors of microsomal prostaglandin E2 synthase-1 (mPGES-1) are being developed as alternative analgesics that are less likely to elicit cardiovascular hazards than cyclooxygenase-2 selective nonsteroidal anti-inflammatory drugs. We have demonstrated that deletion of mPGES-1 protects inflammatory vascular diseases and promotes post-myocardial infarction survival. The role of mPGES-1 in ß-adrenergic receptor-induced cardiomyopathy is unknown. Here we illustrated that deletion of mPGES-1 alleviated isoproterenol-induced cardiac fibrosis without deteriorating cardiac dysfunction. These results illustrated that targeting mPGES-1 may represent an efficacious approach to the treatment of inflammatory cardiovascular diseases.


Assuntos
Cardiomiopatias/genética , Microssomos/metabolismo , Miocárdio/patologia , Prostaglandina-E Sintases/genética , Receptores Adrenérgicos beta/metabolismo , Remodelação Ventricular/genética , Agonistas Adrenérgicos beta/farmacologia , Animais , Cardiomiopatias/metabolismo , Cardiomiopatias/patologia , Células Cultivadas , Feminino , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Fibrose , Isoproterenol/farmacologia , Masculino , Camundongos Knockout , Microssomos/efeitos dos fármacos , Miocárdio/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Ratos , Ratos Sprague-Dawley , Remodelação Ventricular/efeitos dos fármacos
4.
JCI Insight ; 5(13)2020 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-32641583

RESUMO

Prostaglandin E2 and its cognate EP1-4 receptors play important roles in blood pressure (BP) regulation. Herein, we show that endothelial cell-specific (EC-specific) EP4 gene-knockout mice (EC-EP4-/-) exhibited elevated, while EC-specific EP4-overexpression mice (EC-hEP4OE) displayed reduced, BP levels compared with the control mice under both basal and high-salt diet-fed conditions. The altered BP was completely abolished by treatment with l-NG-nitro-l-arginine methyl ester (l-NAME), a competitive inhibitor of endothelial nitric oxide synthase (eNOS). The mesenteric arteries of the EC-EP4-/- mice showed increased vasoconstrictive response to angiotensin II and reduced vasorelaxant response to acetylcholine, both of which were eliminated by l-NAME. Furthermore, EP4 activation significantly reduced BP levels in hypertensive rats. Mechanistically, EP4 deletion markedly decreased NO contents in blood vessels via reducing eNOS phosphorylation at Ser1177. EP4 enhanced NO production mainly through the AMPK pathway in cultured ECs. Collectively, our findings demonstrate that endothelial EP4 is essential for BP homeostasis.


Assuntos
Pressão Sanguínea/fisiologia , Endotélio Vascular/metabolismo , Homeostase/fisiologia , Óxido Nítrico Sintase Tipo III/metabolismo , Receptores de Prostaglandina E Subtipo EP4/metabolismo , Animais , Pressão Sanguínea/efeitos dos fármacos , Dinoprostona/metabolismo , Dinoprostona/farmacologia , Células Endoteliais/metabolismo , Homeostase/efeitos dos fármacos , Hipertensão/metabolismo , Camundongos Transgênicos , NG-Nitroarginina Metil Éster/metabolismo , NG-Nitroarginina Metil Éster/farmacologia
5.
Arterioscler Thromb Vasc Biol ; 40(6): 1523-1532, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32321308

RESUMO

OBJECTIVE: Although the molecular components of circadian rhythms oscillate in discrete cellular components of the vasculature and many aspects of vascular function display diurnal variation, the cellular connections between the molecular clock and inflammatory cardiovascular diseases remain to be elucidated. Previously we have shown that pre- versus postnatal deletion of Bmal1 (brain and muscle aryl hydrocarbon receptor nuclear translocator-like 1), the nonredundant core clock gene has contrasting effects on atherogenesis. Here we investigated the effect of myeloid cell Bmal1 deletion on atherogenesis and abdominal aortic aneurysm formation in mice. Approach and Results: Mice lacking Bmal1 in myeloid cells were generated by crossing Bmal1 flox/flox mice with lysozyme 2 promoter-driven Cre recombinase mice on a hyperlipidemic low-density lipoprotein receptor-deficient background and were fed on a high-fat diet to induce atherosclerosis. Atherogenesis was restrained, concomitant with a reduction of aortic proinflammatory gene expression in myeloid cell Bmal1 knockout mice. Body weight, blood pressure, blood glucose, triglycerides, and cholesterol were unaltered. Similarly, myeloid cell depletion of Bmal1 also restrained Ang II (angiotensin II) induced formation of abdominal aortic aneurysm in hyperlipidemic mice. In vitro, RNA-Seq analysis demonstrated a proinflammatory response in cultured macrophages in which there was overexpression of Bmal1. CONCLUSIONS: Myeloid cell Bmal1 deletion retards atherogenesis and restrains the formation of abdominal aortic aneurysm and may represent a potential therapeutic target for inflammatory cardiovascular diseases.


Assuntos
Fatores de Transcrição ARNTL/deficiência , Fatores de Transcrição ARNTL/fisiologia , Aneurisma da Aorta Abdominal/prevenção & controle , Aterosclerose/prevenção & controle , Hiperlipidemias/complicações , Células Mieloides/química , Fatores de Transcrição ARNTL/genética , Angiotensina II/farmacologia , Animais , Aneurisma da Aorta Abdominal/induzido quimicamente , Aterosclerose/etiologia , Aterosclerose/patologia , Células Cultivadas , Cruzamentos Genéticos , Dieta Hiperlipídica , Deleção de Genes , Expressão Gênica , Hiperlipidemias/etiologia , Inflamação , Integrases/genética , Macrófagos Peritoneais/química , Macrófagos Peritoneais/fisiologia , Camundongos , Camundongos Knockout , Muramidase/genética , Regiões Promotoras Genéticas/genética , Receptores de LDL/deficiência , Receptores de LDL/genética
6.
Sheng Li Xue Bao ; 71(5): 783-791, 2019 Oct 25.
Artigo em Chinês | MEDLINE | ID: mdl-31646332

RESUMO

Circadian rhythms widely exist in living organisms, and they are regulated by the biological clock. Growing evidence has shown that circadian rhythms are tightly related to the physiological function of the cardiovascular system, including blood pressure, heart rate, metabolism of cardiomyocytes, function of endothelial cells, and vasoconstriction and vasodilation. In addition, disruption of circadian rhythms has been considered as one of the important risk factors for cardiovascular diseases, such as myocardial infarction. This review summarizes the recent research advances in the relationship between circadian clock and cardiovascular diseases, hoping to improve treatment strategies for patients with cardiovascular diseases according to the theory of biological clock.


Assuntos
Doenças Cardiovasculares/fisiopatologia , Relógios Circadianos , Ritmo Circadiano , Pressão Sanguínea , Células Endoteliais/citologia , Frequência Cardíaca , Humanos , Miócitos Cardíacos/metabolismo , Vasoconstrição , Vasodilatação
7.
JCI Insight ; 52019 04 11.
Artigo em Inglês | MEDLINE | ID: mdl-30973828

RESUMO

Recently, by utilizing conventional and tamoxifen inducible Bmal1 (Brain and muscle Arnt-like protein 1) knockout mice, we found that delaying the loss of circadian rhythms to adulthood attenuates the impact on general integrity and survival at least under 12h light/12h dark conditions (LD). To understand further the contribution of Bmal1 in post-natal life under conditions of circadian disruption, we subjected inducible knockout mice (KO) and their littermate controls (Ctrl) to forced desynchrony protocols including cycles with non-24h periods, randomized light/dark cycles, and jet lag, and monitored their locomotor activity using radiotelemetry. Under these conditions, control mice cannot be entrained, as reflected by their maintenance of circadian behavior irrespective of schedules. By contrast, KO mice displayed higher activity levels in the dark phases of most cycles. Under a 3h light/3h dark regime, Ctrls displayed higher activity levels in the dark phases of all cycles although there were still obvious circadian rhythms, suggesting that an ultradian mechanism is also involved. Insulin sensitivity was markedly reduced by disrupted light schedules as expected in Ctrls, but not in the KOs. Thus, Bmal1 deletion in adult mice facilitates adaptation to new light/dark schedules and protects from insulin resistance induced by circadian disruption.


Assuntos
Fatores de Transcrição ARNTL/metabolismo , Adaptação Fisiológica , Transtornos Cronobiológicos/fisiopatologia , Ritmo Circadiano/fisiologia , Locomoção/fisiologia , Fatores de Transcrição ARNTL/genética , Animais , Transtornos Cronobiológicos/etiologia , Modelos Animais de Doenças , Humanos , Resistência à Insulina/fisiologia , Masculino , Camundongos , Camundongos Knockout , Fotoperíodo , Tolerância ao Trabalho Programado/fisiologia
8.
J Pharmacol Exp Ther ; 370(1): 18-24, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30992314

RESUMO

Selective deletion of microsomal prostaglandin E2 synthase-1 (mPges-1) in myeloid cells retards atherogenesis and suppresses the vascular proliferative response to injury, while it does not predispose to thrombogenesis or hypertension. However, studies using bone marrow transplants from irradiated mice suggest that myeloid cell mPGES-1 facilitates cardiac remodeling and prolongs survival after experimental myocardial infarction (MI). Here, we addressed this question using mice lacking mPges-1 in myeloid cells, particularly macrophages [Mac-mPges-1-knockout (KO)], generated by crossing mPges-1 floxed mice with LysMCre mice and subjecting them to coronary artery ligation. Cardiac structure and function were assessed by morphometric analysis, echocardiography, and invasive hemodynamics 3, 7, and 28 days after MI. Despite a similar infarct size, in contrast to the prior report, the post-MI survival rate was markedly improved in the Mac-mPges-1-KO mice compared with wild-type controls. Left ventricular systolic (reflected by ejection fraction, fractional shortness end systolic volume, and +dP/dt) and diastolic function (reflected by end diastolic volume, -dP/dt, and Tau), cardiac hypertrophy (reflected by left ventricular dimensions), and staining for fibrosis did not differ between the groups. In conclusion, we found that Cre-loxP-mediated deletion of mPges-1 in myeloid cells has favorable effects on post-MI survival, with no detectable adverse influence on post-MI remodeling. These results add to evidence that targeting macrophage mPGES-1 may represent a safe and efficacious approach to the treatment and prevention of cardiovascular inflammatory disease.


Assuntos
Deleção de Genes , Células Mieloides/metabolismo , Infarto do Miocárdio/genética , Infarto do Miocárdio/patologia , Prostaglandina-E Sintases/genética , Doença Aguda , Animais , Apoptose/genética , Técnicas de Inativação de Genes , Camundongos , Remodelação Ventricular/genética
9.
Arterioscler Thromb Vasc Biol ; 38(12): 2819-2826, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30571171

RESUMO

Objective- Evening but not morning administration of low-dose aspirin has been reported to lower blood pressure in hypertensive patients. The present study was designed to determine whether this phenomenon could be replicated in mice, and if so, whether a time-dependent effect of aspirin on blood pressure was because of alteration of circadian clock function. Approach and Results- We recapitulated the protective effect of aspirin (50 µg/d for 7 days) at zeitgeber time 0 (active-to-rest transit), but not at zeitgeber time 12, on a high-salt diet-induced increase of blood pressure. However, the time of aspirin administration did not influence expression of canonical clock genes or their acetylation. We used mouse Bmal1 and Per2-luciferase reporters expressed in U2OS cells to determine the real-time effect of aspirin on circadian function but found that the oscillation of bioluminescence was unaltered. Timing of aspirin administration also failed to alter urinary prostaglandin metabolites or catecholamines, or the acetylation of its COX-1 (cyclooxygenase-1) target in platelets. Conclusions- The time-dependent hypotensive effect of aspirin in humans has been recapitulated in hypertensive mice. However, this does not seem to reflect a direct impact of aspirin on circadian clocks or on acetylation of platelet COX-1.


Assuntos
Anti-Hipertensivos/administração & dosagem , Aspirina/administração & dosagem , Pressão Sanguínea/efeitos dos fármacos , Ritmo Circadiano , Hipertensão/prevenção & controle , Fatores de Transcrição ARNTL/genética , Fatores de Transcrição ARNTL/metabolismo , Animais , Plaquetas/efeitos dos fármacos , Plaquetas/enzimologia , Linhagem Celular Tumoral , Relógios Circadianos/efeitos dos fármacos , Relógios Circadianos/genética , Ritmo Circadiano/efeitos dos fármacos , Ciclo-Oxigenase 1/sangue , Modelos Animais de Doenças , Cronoterapia Farmacológica , Humanos , Hipertensão/genética , Hipertensão/metabolismo , Hipertensão/fisiopatologia , Masculino , Proteínas de Membrana/sangue , Camundongos Endogâmicos C57BL , Proteínas Circadianas Period/genética , Proteínas Circadianas Period/metabolismo , Cloreto de Sódio na Dieta , Fatores de Tempo
10.
Kidney Blood Press Res ; 43(4): 1297-1309, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30099449

RESUMO

BACKGROUND/AIMS: In clinic, excessive acetaminophen (APAP) can cause kidney damage with uncertain mechanisms. Recently, accumulating evidence demonstrated a pathogenic role of mitochondrial dysfunction in the kidney injury. Thus, in this study, rotenone, a mitochondrial complex I inhibitor, was applied to the mice with APAP-induced acute kidney injury to evaluate the effect of mitochondrial complex I inhibition on APAP nephrotoxicity. METHODS: After 3 days of rotenone pretreatment, mice were administered with APAP (300mg/kg) by intraperitoneal injection for 24 h. Then the kidney injury, inflammation, and oxidative stress were evaluated. RESULTS: APAP significantly enhanced the BUN, serum creatine, and cystatin C levels in line with a moderate alteration of renal morphology. Strikingly, rotenone treatment normalized BUN, serum creatinine, and cystatin C levels, as well as the kidney morphology. Meanwhile, APAP enhanced tubular injury markers of NGAL and KIM-1 by 347- and 5-fold at mRNA levels, respectively. By Western blotting, we confirmed a 15-fold increment of NGAL in APAP-exposed kidneys. Importantly, rotenone treatment largely normalized NGAL and KIM-1 levels and attenuated inflammatory response in APAP-treated mice. Similarly, rotenone treatment enhanced the expressions of SOD1-3 compared with APAP group in line with a significant suppression of kidney MDA content. Finally, we observed that inhibition of mitochondrial complex III failed to protect against APAP-induced nephrotoxicity. CONCLUSION: Mitochondrial complex I inhibitor rotenone protected kidneys against APAP-induced injury possibly via the inhibition of mitochondrial oxidative stress and inflammation.


Assuntos
Injúria Renal Aguda/prevenção & controle , Inflamação/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Rotenona/uso terapêutico , Acetaminofen/efeitos adversos , Injúria Renal Aguda/induzido quimicamente , Animais , Complexo I de Transporte de Elétrons/antagonistas & inibidores , Camundongos , Substâncias Protetoras , Rotenona/farmacologia , Desacopladores/farmacologia , Desacopladores/uso terapêutico
11.
Heart Vessels ; 33(11): 1411-1422, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29796776

RESUMO

Endothelial cells (ECs) are crucial in maintaining vascular homeostasis. Endothelial dysfunction was involved in many cardiovascular diseases (CVDs). Recently, antimalarial medicine artemisinin and its derivatives including dihydroartemisinin (DHA) were found to be beneficial in some diseases including CVDs. Prostaglandin (PG) E2 is a known inflammatory mediator and plays important roles in cardiovascular system. This study was to investigate the role of DHA in regulating cyclooxygenase (COX)/PGE synthase (PGES)/PGE2 cascade and inflammation in ECs. After DHA treatment, the mRNA and protein levels of COX-2 were strikingly upregulated in time- and dose-dependent manners. In contrast, COX-1 was significantly downregulated. As expected, inhibition of COX-1 or COX-2 further reduced PGE2 production after DHA treatment. Moreover, DHA enhanced microsomal PGE2 synthase (mPGES)-2 and moderately modulated cytosolic PGE2 synthase (cPGES) with no effect on mPGES-1 expression. Importantly, DHA significantly reduced PGE2 levels in line with the upregulation of 15-hydroxyprostaglandin dehydrogenase (15-PGDH, a key enzyme for prostaglandin degradation). Lastly, we observed that DHA not only reduced the PGE2 levels in tumor necrosis factor-α (TNF-α)-treated ECs but also blunted the upregulation of inflammatory cytokines of interleukin (IL)-6 and IL-1ß induced by TNF-α or PGE2. These findings demonstrated an important role of DHA in regulating PGE2 synthesis cascade and inflammation in ECs, suggesting a potential of DHA for the treatment of inflammatory vascular diseases.


Assuntos
Artemisininas/farmacologia , Endotélio Vascular/metabolismo , Prostaglandinas E/genética , RNA/genética , Animais , Aorta Torácica/metabolismo , Aorta Torácica/patologia , Western Blotting , Células Cultivadas , Modelos Animais de Doenças , Endotélio Vascular/patologia , Ensaio de Imunoadsorção Enzimática , Camundongos , Prostaglandinas E/biossíntese , Reação em Cadeia da Polimerase em Tempo Real
12.
Oncotarget ; 9(10): 9235-9245, 2018 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-29507686

RESUMO

COX-2/mPGES-1/PGE2 cascade is of importance in the pathogenesis of kidney injury. Meanwhile, recent studies documented a detrimental role of mitochondrial oxidative stress in kidney diseases. The present study was undertaken to investigate the role of mitochondrial oxidative stress in albumin-induced activation of COX-2/mPGES-1/PGE2 cascade in renal proximal tubular cells. Following albumin overload in mice, we observed a significant increase of oxidative stress and mitochondrial abnormality determined by transmission electron microscope, which was attenuated by the administration of MnTBAP, a mitochondrial SOD2 mimic. More interestingly, albumin overload-induced upregulation of COX-2 and mPGES-1 at mRNA and protein levels was largely abolished by MnTBAP treatment in mice. Meanwhile, urinary PGE2 excretion was also blocked by MnTBAP treatment. Furthermore, mouse proximal tubule epithelial cells (mPTCs) were treated with albumin. Similarly, COX-2/mPGES-1/PGE2 cascade was significantly activated by albumin in dose- and time-dependent manners, which was abolished by MnTBAP treatment in parallel with a blockade of oxidative stress. Collectively, the findings from current study demonstrated that mitochondrial oxidative stress could activate COX-2/mPGES-1/PGE2 cascade in proximal tubular cells under the proteinuria condition. Mitochondrial oxidative stress/COX-2/mPGES-1/PGE2 could serve as the important targets for the treatment of proteinuria-associated kidney injury.

13.
Artigo em Inglês | MEDLINE | ID: mdl-29104159

RESUMO

Prostaglandin E2 (PGE2) is the most abundant prostanoid synthesized in the kidney and plays an important role in renal function. Physiologically, PGE2 regulates renal hemodynamics, water and sodium metabolism, blood pressure, and so on. As a well-known proinflammatory lipid mediator, PGE2 also substantially mediates renal injury under many pathophysiological conditions. Multiple enzymes are involved in renal PGE2 biosynthesis, including the three main PGE2 terminal synthases, i.e. microsomal PGE2 synthase-1 (mPGES-1), mPGES-2 and cytosolic PGE2 synthase (cPGES). In the kidney, mPGES-1 is highly expressed in the collecting duct where it is the dominant contributor of PGE2 biosynthesis and participates in blood pressure regulation and renal hemodynamic maintenance. mPGES-2 protein is mainly expressed in the renal cortex and the outer stripe of the outer medulla. cPGES is diffusely expressed in all nephron segments. Roles of mPGES-2 and cPGES in renal function have not been clearly characterized. Here we summarize the role of PGE2 in the kidney, highlight the contribution of the three PGE2 synthases, particularly mPGES-1, in blood pressure regulation and renal hemodynamics, and outline the contribution of mPGES-1 to kidney diseases. A clearer understanding of the role of PGE2 in the kidney could pave the way for development of new therapeutic approaches.


Assuntos
Dinoprostona/metabolismo , Prostaglandina-E Sintases/metabolismo , Animais , Pressão Sanguínea , Humanos , Rim/metabolismo , Rim/fisiologia , Rim/fisiopatologia , Sódio/metabolismo , Água/metabolismo
14.
Sci Rep ; 7(1): 17141, 2017 12 07.
Artigo em Inglês | MEDLINE | ID: mdl-29215023

RESUMO

Physiological function, disease expression and drug effects vary by time-of-day. Clock disruption in mice results in cardio-metabolic, immunological and neurological dysfunction; circadian misalignment using forced desynchrony increases cardiovascular risk factors in humans. Here we integrated data from remote sensors, physiological and multi-omics analyses to assess the feasibility of detecting time dependent signals - the chronobiome - despite the "noise" attributable to the behavioral differences of free-living human volunteers. The majority (62%) of sensor readouts showed time-specific variability including the expected variation in blood pressure, heart rate, and cortisol. While variance in the multi-omics is dominated by inter-individual differences, temporal patterns are evident in the metabolome (5.4% in plasma, 5.6% in saliva) and in several genera of the oral microbiome. This demonstrates, despite a small sample size and limited sampling, the feasibility of characterizing at scale the human chronobiome "in the wild". Such reference data at scale are a prerequisite to detect and mechanistically interpret discordant data derived from patients with temporal patterns of disease expression, to develop time-specific therapeutic strategies and to refine existing treatments.


Assuntos
Ritmo Circadiano , Metaboloma , Microbiota , Proteoma , Transcriptoma , Adulto , Pressão Sanguínea , Proteínas Sanguíneas/metabolismo , Frequência Cardíaca , Humanos , Hidrocortisona/metabolismo , Masculino , Boca/metabolismo , Projetos Piloto , Saliva/metabolismo , Fatores de Tempo
15.
Oncotarget ; 8(44): 75808-75821, 2017 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-29100270

RESUMO

Renal resistance to loop diuretics is a frequent complication in a number of kidney disease patients with elusive mechanism. Employing human renal biopsy specimens, albumin overload mouse model, and primary cultures of mouse renal tubular cells, albuminuria effect on NKCC2 expression and function and the underlying mechanisms were investigated. In the renal biopsy specimens of albuminuric patients, we found that NKCC2 was significantly downregulated with a negative correlation with albuminuria severity as examined by immunohistochemistry. Meanwhile, NLRP3 and mPGES-1 were stimulated in NKCC2 positive tubules (thick ascending limb, TAL) paralleled with increased urinary PGE2 excretion. To examine the role of albuminuria in the downregulation of NKCC2 and the potential role of NLRP3/prostaglandin signaling in NKCC2 downregulation, an albumin overload mouse model was employed. Interestingly, we discovered that albuminuria downregulated NKCC2 protein expression in murine kidney and impaired the renal response to loop diuretic furosemide. Specifically, albuminuria suppressed NKCC2 expression and function through NLRP3/prostaglandin dependent signaling in TAL. In primary cultures of renal tubular cells, albumin directly reduced NKCC2 but enhanced NLRP3, COX-2, and mPGES-1 expression. These novel findings demonstrated that albuminuria is of importance in mediating the renal resistance to loop diuretics via NLRP3/prostaglandin signaling-dependent NKCC2 downregulation in TAL. This may also offer novel, effective targets for dealing with the resistance of loop diuretics in proteinuric renal diseases.

16.
Oxid Med Cell Longev ; 2016: 5249086, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27594972

RESUMO

Nonsteroidal anti-inflammatory drugs (NSAIDs), especially cyclooxygenase-2 (COX-2) selective inhibitors, are among the most widely used drugs to treat pain and inflammation. However, clinical trials have revealed that these inhibitors predisposed patients to a significantly increased cardiovascular risk, consisting of thrombosis, hypertension, myocardial infarction, heart failure, and sudden cardiac death. Thus, microsomal prostaglandin E (PGE) synthase-1 (mPGES-1), the key terminal enzyme involved in the synthesis of inflammatory prostaglandin E2 (PGE2), and the four PGE2 receptors (EP1-4) have gained much attention as alternative targets for the development of novel analgesics. The cardiovascular consequences of targeting mPGES-1 and the PGE2 receptors are substantially studied. Inhibition of mPGES-1 has displayed a relatively innocuous or preferable cardiovascular profile. The modulation of the four EP receptors in cardiovascular system is diversely reported as well. In this review, we highlight the most recent advances from our and other studies on the regulation of PGE2, particularly mPGES-1 and the four PGE2 receptors, in cardiovascular function, with a particular emphasis on blood pressure regulation, atherosclerosis, thrombosis, and myocardial infarction. This might lead to new avenues to improve cardiovascular disease management strategies and to seek optimized anti-inflammatory therapeutic options.


Assuntos
Doenças Cardiovasculares/metabolismo , Sistema Cardiovascular/metabolismo , Sistema Cardiovascular/patologia , Microssomos/enzimologia , Prostaglandina-E Sintases/metabolismo , Receptores de Prostaglandina/metabolismo , Animais , Doenças Cardiovasculares/fisiopatologia , Sistema Cardiovascular/fisiopatologia , Humanos , Remodelação Vascular
17.
Sci Transl Med ; 8(324): 324ra16, 2016 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-26843191

RESUMO

The absence of Bmal1, a core clock gene, results in a loss of circadian rhythms, an acceleration of aging, and a shortened life span in mice. To address the importance of circadian rhythms in the aging process, we generated conditional Bmal1 knockout mice that lacked the BMAL1 protein during adult life and found that wild-type circadian variations in wheel-running activity, heart rate, and blood pressure were abolished. Ocular abnormalities and brain astrogliosis were conserved irrespective of the timing of Bmal1 deletion. However, life span, fertility, body weight, blood glucose levels, and age-dependent arthropathy, which are altered in standard Bmal1 knockout mice, remained unaltered, whereas atherosclerosis and hair growth improved, in the conditional adult-life Bmal1 knockout mice, despite abolition of clock function. Hepatic RNA-Seq revealed that expression of oscillatory genes was dampened in the adult-life Bmal1 knockout mice, whereas overall gene expression was largely unchanged. Thus, many phenotypes in conventional Bmal1 knockout mice, hitherto attributed to disruption of circadian rhythms, reflect the loss of properties of BMAL1 that are independent of its role in the clock. These findings prompt reevaluation of the systemic consequences of disruption of the molecular clock.


Assuntos
Fatores de Transcrição ARNTL/genética , Envelhecimento/genética , Relógios Circadianos/genética , Regulação da Expressão Gênica , Fatores de Transcrição ARNTL/deficiência , Fatores de Transcrição ARNTL/metabolismo , Animais , Aterosclerose/genética , Aterosclerose/patologia , Glicemia/metabolismo , Ritmo Circadiano/genética , Dieta Hiperlipídica , Anormalidades do Olho/patologia , Fertilidade , Perfilação da Expressão Gênica , Gliose/patologia , Cabelo/crescimento & desenvolvimento , Longevidade , Camundongos Knockout , Fenótipo , Análise de Sobrevida , Fatores de Tempo , Transcriptoma/genética
18.
Am J Physiol Renal Physiol ; 310(6): F492-8, 2016 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-26739892

RESUMO

Podocyte damage is a common pathological feature in many types of glomerular diseases and is involved in the occurrence and progression of kidney disease. However, the pathogenic mechanisms leading to podocyte injury are still uncertain. The present study was undertaken to investigate the role of microsomal PGE synthase (mPGES)-1 in adriamycin (ADR)-induced podocyte injury as well as the underlying mechanism. In both mouse kidneys and in vitro podocytes, application of ADR remarkably enhanced mPGES-1 expression in line with a stimulation of cyclooxygenase-2. Interestingly, inhibition of mPGES-1 with a small interfering RNA approach significantly attenuated ADR-induced downregualtion of podocin and nephrin. Moreover, ADR-induced podocyte apoptosis was also markedly blocked in parallel with blunted caspase-3 induction. In agreement with the improvement of cell phenotypic alteration and apoptosis, the enhanced inflammatory markers of IL-1ß and TNF-α were also significantly suppressed by mPGES-1 silencing. More importantly, in mPGES-1-deficient mice, albuminuria induced by ADR showed a remarkable attenuation in line with decreased urinary output of PGE2 and TNF-α, highly suggesting an in vivo role of mPGES-1 in mediating podocyte injury. In summary, findings from the present study offered the first evidence demonstrating a pathogenic role of mPGES-1 in mediating ADR-induced podocyte injury possibly via triggering an inflammatory response.


Assuntos
Dinoprostona/metabolismo , Doxorrubicina/toxicidade , Oxirredutases Intramoleculares/metabolismo , Nefropatias/etiologia , Podócitos/enzimologia , Animais , Células Cultivadas , Nefropatias/enzimologia , Masculino , Camundongos Endogâmicos BALB C , Podócitos/efeitos dos fármacos , Prostaglandina-E Sintases
20.
Proc Natl Acad Sci U S A ; 112(23): 7231-6, 2015 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-25995365

RESUMO

The response to an innate immune challenge is conditioned by the time of day, but the molecular basis for this remains unclear. In myeloid cells, there is a temporal regulation to induction by lipopolysaccharide (LPS) of the proinflammatory microRNA miR-155 that correlates inversely with levels of BMAL1. BMAL1 in the myeloid lineage inhibits activation of NF-κB and miR-155 induction and protects mice from LPS-induced sepsis. Bmal1 has two miR-155-binding sites in its 3'-UTR, and, in response to LPS, miR-155 binds to these two target sites, leading to suppression of Bmal1 mRNA and protein in mice and humans. miR-155 deletion perturbs circadian function, gives rise to a shorter circadian day, and ablates the circadian effect on cytokine responses to LPS. Thus, the molecular clock controls miR-155 induction that can repress BMAL1 directly. This leads to an innate immune response that is variably responsive to challenges across the circadian day.


Assuntos
Fatores de Transcrição ARNTL/fisiologia , Ritmo Circadiano , Imunidade Inata , Macrófagos/imunologia , MicroRNAs/fisiologia , Regiões 3' não Traduzidas , Fatores de Transcrição ARNTL/genética , Tecido Adiposo/metabolismo , Animais , Citocinas/biossíntese , Macrófagos/metabolismo , Camundongos , Camundongos Knockout , NF-kappa B/metabolismo
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