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1.
J Biol Chem ; 286(22): 19682-92, 2011 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-21478551

RESUMO

With increasing worldwide rates of morbidity and mortality of pulmonary fibrosis, the development of effective therapeutics for this disease is of great interest. Secretoglobin (SCGB) 3A2, a novel cytokine-like molecule predominantly expressed in pulmonary airways epithelium, exhibits anti-inflammatory and growth factor activities. In the current study SCGB3A2 was found to inhibit TGFß-induced differentiation of fibroblasts to myofibroblasts, a hallmark of the fibrogenic process, using pulmonary fibroblasts isolated from adult mice. This induction was through increased phosphorylation of STAT1 and expression of SMAD7 and decreased phosphorylation of SMAD2 and SMAD3. To demonstrate the effect of SCGB3A2 on the TGFß signaling in vivo, a bleomycin-induced pulmonary fibrosis mouse model was used. Mice were administered bleomycin intratracheally followed by intravenous injection of recombinant SCGB3A2. Histological examination in conjunction with inflammatory cell counts in bronchoalveolar lavage fluids demonstrated that SCGB3A2 suppressed bleomycin-induced pulmonary fibrosis. Microarray analysis was carried out using RNAs from lungs of bleomycin-treated mice with or without SCGB3A2 and normal mice treated with SCGB3A2. The results demonstrated that SCGB3A2 affects TGFß signaling and reduces the expression of genes involved in fibrosis. This study suggests the potential utility of SCGB3A2 for targeting TGFß signaling in the treatment of pulmonary fibrosis.


Assuntos
Antibióticos Antineoplásicos/efeitos adversos , Bleomicina/efeitos adversos , Regulação para Baixo/efeitos dos fármacos , Proteínas/metabolismo , Fibrose Pulmonar/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fator de Crescimento Transformador beta/metabolismo , Animais , Antibióticos Antineoplásicos/farmacologia , Bleomicina/farmacologia , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/genética , Regulação para Baixo/genética , Feminino , Fibroblastos/metabolismo , Fibroblastos/patologia , Perfilação da Expressão Gênica , Humanos , Camundongos , Análise de Sequência com Séries de Oligonucleotídeos , Fosforilação/efeitos dos fármacos , Fosforilação/genética , Proteínas/genética , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/patologia , Fator de Transcrição STAT1/genética , Fator de Transcrição STAT1/metabolismo , Secretoglobinas , Transdução de Sinais/genética , Proteínas Smad/genética , Proteínas Smad/metabolismo , Fator de Crescimento Transformador beta/genética
2.
J Biol Chem ; 285(10): 7670-85, 2010 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-20032461

RESUMO

A previous study identified the peroxisome proliferator-activated receptor alpha (PPARalpha) activation biomarkers 21-steroid carboxylic acids 11beta-hydroxy-3,20-dioxopregn-4-en-21-oic acid (HDOPA) and 11beta,20-dihydroxy-3-oxo-pregn-4-en-21-oic acid (DHOPA). In the present study, the molecular mechanism and the metabolic pathway of their production were determined. The PPARalpha-specific time-dependent increases in HDOPA and 20alpha-DHOPA paralleled the development of adrenal cortex hyperplasia, hypercortisolism, and spleen atrophy, which was attenuated in adrenalectomized mice. Wy-14,643 activation of PPARalpha induced hepatic FGF21, which caused increased neuropeptide Y and agouti-related protein mRNAs in the hypothalamus, stimulation of the agouti-related protein/neuropeptide Y neurons, and activation of the hypothalamic-pituitary-adrenal (HPA) axis, resulting in increased adrenal cortex hyperplasia and corticosterone production, revealing a link between PPARalpha and the HPA axis in controlling energy homeostasis and immune regulation. Corticosterone was demonstrated as the precursor of 21-carboxylic acids both in vivo and in vitro. Under PPARalpha activation, the classic reductive metabolic pathway of corticosterone was suppressed, whereas an alternative oxidative pathway was uncovered that leads to the sequential oxidation on carbon 21 resulting in HDOPA. The latter was then reduced to the end product 20alpha-DHOPA. Hepatic cytochromes P450, aldehyde dehydrogenase (ALDH3A2), and 21-hydroxysteroid dehydrogenase (AKR1C18) were found to be involved in this pathway. Activation of PPARalpha resulted in the induction of Aldh3a2 and Akr1c18, both of which were confirmed as target genes through introduction of promoter luciferase reporter constructs into mouse livers in vivo. This study underscores the power of mass spectrometry-based metabolomics combined with genomic and physiologic analyses in identifying downstream metabolic biomarkers and the corresponding upstream molecular mechanisms.


Assuntos
Biomarcadores/metabolismo , Hidroxiprogesteronas/metabolismo , Sistema Hipotálamo-Hipofisário/fisiologia , PPAR alfa/metabolismo , Sistema Hipófise-Suprarrenal/fisiologia , Progestinas/metabolismo , Corticosteroides/metabolismo , Adrenalectomia , Oxirredutases do Álcool/metabolismo , Aldeído Oxirredutases/genética , Aldeído Oxirredutases/metabolismo , Animais , Biomarcadores/química , Jejum , Hidroxiprogesteronas/química , Fígado/metabolismo , Masculino , Espectrometria de Massas , Metabolômica , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Estrutura Molecular , Análise de Sequência com Séries de Oligonucleotídeos , Oxirredução , PPAR alfa/genética , Proliferadores de Peroxissomos/administração & dosagem , Proliferadores de Peroxissomos/metabolismo , Progestinas/química , Pirimidinas/administração & dosagem , Pirimidinas/metabolismo , Urina/química
3.
Bioorg Med Chem Lett ; 21(7): 1978-82, 2011 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-21377875

RESUMO

In our search for new PPARα/γ agonists, we designed and synthesized a series of benzoylazole-based carboxylic acids. Compound 9 showed potent PPARγ partial agonistic activity with modest PPARα agonistic activity. The sodium salt of 9 (9Na) demonstrated potent efficacy in lowering both blood glucose and lipids in an animal model without causing significant body weight gain, a well-known side effect associated with PPARγ full agonists.


Assuntos
Azóis/síntese química , Azóis/farmacologia , PPAR alfa/agonistas , PPAR gama/agonistas , Animais , Azóis/química , Humanos , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Hipolipemiantes/química , Hipolipemiantes/farmacologia , Camundongos , Modelos Animais , Modelos Moleculares
4.
Nat Commun ; 12(1): 290, 2021 01 12.
Artigo em Inglês | MEDLINE | ID: mdl-33436590

RESUMO

The environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) causes hepatic toxicity associated with prominent lipid accumulation in humans. Here, the authors report that the lysosomal copper transporter SLC46A3 is induced by TCDD and underlies the hepatic lipid accumulation in mice, potentially via effects on mitochondrial function. SLC46A3 was localized to the lysosome where it modulated intracellular copper levels. Forced expression of hepatic SLC46A3 resulted in decreased mitochondrial membrane potential and abnormal mitochondria morphology consistent with lower copper levels. SLC46A3 expression increased hepatic lipid accumulation similar to the known effects of TCDD exposure in mice and humans. The TCDD-induced hepatic triglyceride accumulation was significantly decreased in Slc46a3-/- mice and was more pronounced when these mice were fed a high-fat diet, as compared to wild-type mice. These data are consistent with a model where lysosomal SLC46A3 induction by TCDD leads to cytosolic copper deficiency resulting in mitochondrial dysfunction leading to lower lipid catabolism, thus linking copper status to mitochondrial function, lipid metabolism and TCDD-induced liver toxicity.


Assuntos
Proteínas de Transporte de Cobre/metabolismo , Cobre/metabolismo , Citosol/metabolismo , Homeostase , Lisossomos/metabolismo , Transportador de Folato Acoplado a Próton/metabolismo , Animais , Proteínas de Transporte de Cobre/genética , Citosol/efeitos dos fármacos , Proteínas de Fluorescência Verde/metabolismo , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Hepatócitos/ultraestrutura , Homeostase/efeitos dos fármacos , Íons , Fígado/metabolismo , Lisossomos/efeitos dos fármacos , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Modelos Biológicos , Dibenzodioxinas Policloradas/toxicidade , Transportador de Folato Acoplado a Próton/genética , Receptores de Hidrocarboneto Arílico/metabolismo , Especificidade por Substrato/efeitos dos fármacos , Superóxido Dismutase/metabolismo , Triglicerídeos/metabolismo
5.
Toxicol Sci ; 101(1): 132-9, 2008 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-17690133

RESUMO

To determine the impact of the species difference between rodents and humans in response to peroxisome proliferators (PPs) mediated by peroxisome proliferator-activated receptor (PPAR)alpha, PPAR alpha-humanized transgenic mice were generated using a P1 phage artificial chromosome (PAC) genomic clone bred onto a ppar alpha-null mouse background, designated hPPAR alpha PAC. In hPPAR alpha PAC mice, the human PPAR alpha gene is expressed in tissues with high fatty acid catabolism and induced upon fasting, similar to mouse PPAR alpha in wild-type (Wt) mice. Upon treatment with the PP fenofibrate, hPPAR alpha PAC mice exhibited responses similar to Wt mice, including peroxisome proliferation, lowering of serum triglycerides, and induction of PPAR alpha target genes encoding enzymes involved in fatty acid metabolism in liver, kidney, and heart, suggesting that human PPAR alpha (hPPAR alpha) functions in the same manner as mouse PPAR alpha in regulating fatty acid metabolism and lowering serum triglycerides. However, in contrast to Wt mice, treatment of hPPAR alpha PAC mice with fenofibrate did not cause significant hepatomegaly and hepatocyte proliferation, thus indicating that the mechanisms by which PPAR alpha affects lipid metabolism are distinct from the hepatocyte proliferation response, the latter of which is only induced by mouse PPAR alpha. In addition, a differential regulation of several genes, including the oncogenic let-7C miRNA by PPs, was observed between Wt and hPPAR alpha PAC mice that may contribute to the inherent difference between mouse and human PPAR alpha in activation of hepatocellular proliferation. The hPPAR alpha PAC mouse model provides an in vivo platform to investigate the species difference mediated by PPAR alpha and an ideal model for human risk assessment PPs exposure.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas/patologia , PPAR alfa/fisiologia , Animais , Antimetabólitos , Northern Blotting , Bromodesoxiuridina , Proliferação de Células/efeitos dos fármacos , Cromossomos Artificiais Humanos/genética , Clonagem Molecular , Fenofibrato/farmacologia , Humanos , Hipolipemiantes/farmacologia , Lipídeos/sangue , Camundongos , Camundongos Transgênicos , Mitocôndrias Hepáticas/metabolismo , Modelos Biológicos , RNA/biossíntese , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Especificidade da Espécie
6.
Ren Fail ; 26(1): 5-11, 2004 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-15083915

RESUMO

Hepatocyte growth factor (HGF) is known to have beneficial effects against damage in various organs, including liver, kidney and lung, in disease models. Previously, we reported that repeated administration of HGF ameliorates renal dysfunction and histological alteration of glycerol-injected rats, an animal model for severe acute renal failure (ARF). In the present study, we investigated in more detail the efficacy of pre- and post-treatment of HGF in this model. ARF was induced by intramuscular injection of glycerol into the hind limbs of male Wistar rats. The efficacy of pre-treatment was studied by intravenous injection of HGF (1 mg/kg) or vehicle 1 and 18 hours prior to glycerol injection. Pre-treatment of HGF dramatically protected glycerol-induced ARF rats against death, and prevented deterioration of biochemical parameters for renal function. We also analyzed expression of heme oxygenase-1 (HO-1), a cytoprotective protein, in kidney of HGF-injected rats. Intravenous administration of HGF enhanced renal expression of HO-1 mRNA from 1 to 3 hours after injection. Next, as a post-treatment study, HGF (1 mg/kg/3 hours) with dopamine was infused into glycerol-induced ARF rats 7 hours after glycerol injection. Intravenous infusion of HGF after ARF onset also ameliorated renal biochemical parameters. These results indicate that pre-treatment of HGF can improve ARF, and induction of HO-1 expression in kidney may be a cause of the protective effect. In addition, post-treatment of HGF with dopamine was also effective against the establishment of ARF.


Assuntos
Injúria Renal Aguda/tratamento farmacológico , Injúria Renal Aguda/enzimologia , Heme Oxigenase (Desciclizante)/metabolismo , Fator de Crescimento de Hepatócito/uso terapêutico , Rim/enzimologia , Mitógenos/uso terapêutico , Injúria Renal Aguda/induzido quimicamente , Animais , Modelos Animais de Doenças , Regulação Enzimológica da Expressão Gênica , Glicerol , Heme Oxigenase (Desciclizante)/genética , Heme Oxigenase-1 , Fator de Crescimento de Hepatócito/fisiologia , Masculino , Mitógenos/fisiologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Wistar
7.
Nephron ; 91(4): 730-8, 2002 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-12138279

RESUMO

BACKGROUND/AIMS: Hepatocyte growth factor (HGF), a multi-potent growth factor, is known to promote regeneration of damaged renal epithelial cells. Glycerol injection into rats induces severe acute renal failure (ARF) with ischemia and tubular necrosis, a model which shares many features with human ARF or rhabdomyolysis. We investigated the efficacy of HGF in this glycerol-induced ARF rat model. METHODS: ARF was induced by intramuscular injection of glycerol into the hind limbs of male Wistar rats. HGF (0.25 mg/kg/shot) or vehicle was administered intravenously 1 h before and 1, 3, 5, 8, 24 and 36 h after glycerol injection. Biochemical parameters for serum and urine were measured and histological analyses of the kidneys were performed. We also analyzed endogenous HGF expression and phosphorylation of c-Met/HGF receptor in the kidneys of glycerol-induced ARF rats. RESULTS: Glycerol treatment caused severe ARF which invariably led to death of the rats. Repeated administration of HGF protected rats from death caused by severe ARF. Histological analyses revealed that HGF treatment reduced necrosis of tubular cells in the renal cortex. Serum/urine biochemical parameters also showed that renal dysfunction was improved by HGF administration. Intravenous administration of HGF enhanced phosphorylation of the c-Met/HGF receptor and mitogen-activated protein kinase in the kidney. In the vehicle-treated group the renal endogenous HGF concentration decreased and there was no change in c-Met/HGF receptor phosphorylation. CONCLUSION: These results indicate that HGF effectively accelerated the recovery of renal function and improved survival in glycerol-induced ARF rats.


Assuntos
Glicerol/toxicidade , Fator de Crescimento de Hepatócito/uso terapêutico , Túbulos Renais/patologia , Insuficiência Renal/tratamento farmacológico , Doença Aguda , Animais , Masculino , Necrose , Ratos , Ratos Wistar , Proteínas Recombinantes/uso terapêutico , Insuficiência Renal/induzido quimicamente
8.
J Vasc Surg ; 35(4): 786-91, 2002 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-11932680

RESUMO

PURPOSE: The major cause of vascular prosthesis failure is anastomotic intimal hyperplasia caused by the proliferation and migration of smooth muscle cells. Hepatocyte growth factor (HGF) is an endothelium-specific growth factor that exerts a mitogenic action on endothelial cells. This study was designed to examine the effect of HGF on the suppression of intimal hyperplasia after small-caliber expanded polytetrafluoroethylene (ePTFE) grafting. METHODS: An ePTFE graft, 2 mm in diameter and 30 mm in length, was implanted in the left common carotid arteries of Japanese white rabbits, after which the animals were fed with a 1.0% cholesterol diet. HGF was infused intravenously immediately and then every day for 7 days at doses of 0.3 mg/body (the 0.3-mg HGF group; n = 20) or 1.0 mg/body (the 1.0-mg HGF group; n = 17). A control group (n = 20) underwent infusion with saline solution. The rabbits were killed on postoperative days (PODs) 1, 2, 3, 5, 7, and 28. RESULTS: The patency rates on POD 28 were 33%, 55%, and 100% in the control, the 0.3-mg HGF, and the 1.0-mg HGF groups, respectively, with a significant difference between the control and the 1.0-mg HGF group (P <.05). Endothelial-like cells were seen on the intraluminal surface of the graft only near the anastomotic site on POD 5 in the 1.0-mg HGF group. Intimal thickness at the distal anastomosis was 284 +/- 140 microm, 106 +/- 18 microm, and 67 +/- 10 microm in the control, the 0.3-mg HGF, and the 1.0-mg HGF groups, respectively, with a significant difference between the control and both HGF groups (P <.05). The number of anti-embryonic smooth muscle antibody positive cells at the distal anastomosis was 28.6 +/- 0.8, 3.8 +/- 2.8, and 3.9 +/- 0.9 in the control, the 0.3-mg HGF, and the 1.0-mg HGF groups, respectively, with a significant difference between the control and both HGF groups (P <.01). CONCLUSION: HGF might suppress intimal thickness at the anastomotic site and improve the patency rate via rapid reendothelialization by POD 28 in a rabbit carotid ePTFE grafting model.


Assuntos
Prótese Vascular , Artéria Carótida Primitiva/patologia , Fator de Crescimento de Hepatócito/farmacologia , Politetrafluoretileno , Túnica Íntima/patologia , Animais , Implante de Prótese Vascular , Artéria Carótida Primitiva/cirurgia , Colesterol na Dieta/administração & dosagem , Hiperplasia/patologia , Masculino , Músculo Liso Vascular/patologia , Coelhos , Grau de Desobstrução Vascular
9.
Nephron ; 90(2): 195-205, 2002 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-11818705

RESUMO

Hepatocyte growth factor (HGF) enhances proliferation of renal epithelial cells as well as hepatocytes. HGF accelerates recovery from acute renal failure (ARF) in animal models. However, pharmacological profiles of HGF including its action mechanism has not been studied in detail. An HgCl(2)-induced ARF mouse was used in this study to evaluate the efficacy of HGF. Single administrations of recombinant human HGF or vehicle were given to ARF mice 30 min after HgCl(2) injection. Renal function was monitored by measuring serum creatinine, blood urea nitrogen and creatinine clearance. In the ARF mice, there was a deterioration of renal function biochemical parameters and histological evidence of renal damage including acute tubular necrosis of proximal tubules. These were both significantly ameliorated by a single HGF administration. The effect of HGF was noticeable in the early phase of ARF (1 day after onset) when there was no histological evidence of increased labeling indexes in renal tubular epithelial cells. Western blot analysis of the c-Met/HGF receptor showed that tyrosine phosphorylation was enhanced immediately after HGF administration indicating direct activation of renal epithelial cells. HGF prevented increase of apoptotic nuclei with DNA fragmentation in renal epithelial cells which suggests cytoprotective activity of HGF on renal epithelial cells in the ARF mice.


Assuntos
Injúria Renal Aguda/tratamento farmacológico , Fator de Crescimento de Hepatócito/farmacologia , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/patologia , Animais , Apoptose/efeitos dos fármacos , Nitrogênio da Ureia Sanguínea , Divisão Celular/efeitos dos fármacos , Creatinina/sangue , Creatinina/urina , Desinfetantes , Relação Dose-Resposta a Droga , Células Epiteliais/patologia , Fator de Crescimento de Hepatócito/sangue , Injeções Intravenosas , Rim/patologia , Masculino , Cloreto de Mercúrio , Camundongos , Camundongos Endogâmicos BALB C
10.
Surg Today ; 32(7): 618-22, 2002.
Artigo em Inglês | MEDLINE | ID: mdl-12111519

RESUMO

PURPOSE: To evaluate whether nonpenetrating vascular closure staples (VCS) and hepatocyte growth factor (HGF) can effectively prevent anastomotic intimal hyperplasia. METHODS: An expanded polytetrafluoroethylene graft, 2 mm in diameter, was implanted in the common carotid artery of rabbits divided into three experimental groups. In the control group, distal anastomosis was performed with interrupted suturing; in the VCS group, clips were applied along the lateral suture line after the placement of stay sutures; and in the VCS + HGF group, the same anastomotic technique was performed as in the VCS group, followed by the administration of the HGF for 4 days. RESULTS: The time taken to complete the anastomosis was significantly less in both the VCS groups than in the control group ( P < 0.0001). On postoperative day (POD) 28, the patency rate was significantly lower ( P < 0.05) in the VCS group (42.9%) than in the control group (100%), but the rate in the VCS + HGF group (100%) was the same as that in the control group. Intimal thickness was significantly less in the control group than in either the VCS or VCS + HGF groups ( P< 0.05). The percentage of area stenosis was significantly less ( P< 0.01) in the control group than in the VCS group. CONCLUSION: The VCS clip failed to suppress intimal thickness or reduce the percentage of stenosis at the anastomotic site.


Assuntos
Implante de Prótese Vascular , Reação a Corpo Estranho/prevenção & controle , Fator de Crescimento de Hepatócito/farmacologia , Complicações Pós-Operatórias/prevenção & controle , Suturas , Túnica Íntima/patologia , Anastomose Cirúrgica , Animais , Artérias Carótidas/cirurgia , Constrição Patológica/prevenção & controle , Fator de Crescimento de Hepatócito/administração & dosagem , Hiperplasia , Politetrafluoretileno , Coelhos , Técnicas de Sutura
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