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1.
Biomedicines ; 12(2)2024 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-38397964

RESUMO

Autosomal Dominant Polycystic Kidney Disease (ADPKD) stands as the most prevalent hereditary renal disorder in humans, ultimately culminating in end-stage kidney disease. Animal models carrying mutations associated with polycystic kidney disease have played an important role in the advancement of ADPKD research. The Han:SPRD rat model, carrying an R823W mutation in the Anks6 gene, is characterized by cyst formation and kidney enlargement. The mutated protein, named Samcystin, is localized in cilia of tubular epithelial cells and seems to be involved in cystogenesis. The homozygous Anks6 mutation leads to end-stage renal disease and death, making it a critical factor in kidney development and function. This review explores the utility of the Han:SPRD rat model, highlighting its phenotypic similarity to human ADPKD. Specifically, we discuss its role in preclinical trials and its importance for investigating the pathogenesis of the disease and developing new therapeutic approaches.

2.
Theranostics ; 11(12): 5939-5954, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33897891

RESUMO

Aims: We previously found that complement components are upregulated in the myocardium of patients with arrhythmogenic right ventricular cardiomyopathy (ARVC), and inhibiting the complement receptor C5aR reduces disease severity in desmin knockout (Des-/- ) mice, a model for ARVC. Here, we examined the mechanism underlying complement activation in ARVC, revealing a potential new therapeutic target. Methods: First, immunostaining, RT-PCR and western blot were used to detect the expression levels of complement and coagulation factors. Second, we knocked out the central complement component C3 in Des-/- mice (ARVC model) by crossing Des-/- mice with C3-/- mice to explore whether complement system activation occurs independently of the conventional pathway. Then, we evaluated whether a targeted intervention to coagulation system is effective to reduce myocardium injury. Finally, the plasma sC5b9 level was assessed to investigate the role in predicting adverse cardiac events in the ARVC cohort. Results: The complement system is activated in the myocardium in ARVC. Autoantibodies against myocardial proteins provided a possible mechanism underlying. Moreover, we found increased levels of myocardial C5 and the serum C5a in Des-/-C3-/- mice compared to wild-type mice, indicating that C5 is activated independently from the conventional pathway, presumably via the coagulation system. Crosstalk between the complement and coagulation systems exacerbated the myocardial injury in ARVC mice, and this injury was reduced by using the thrombin inhibitor lepirudin. In addition, we found significantly elevated plasma levels of sC5b9 and thrombin in patients, and this increase was correlated with all-cause mortality. Conclusions: These results suggest that crosstalk between the coagulation and complement systems plays a pathogenic role in cardiac dysfunction in ARVC. Thus, understanding this crosstalk may have important clinical implications with respect to diagnosing and treating ARVC.


Assuntos
Coagulação Sanguínea/imunologia , Ativação do Complemento/imunologia , Ventrículos do Coração/imunologia , Miocárdio/imunologia , Adulto , Animais , Displasia Arritmogênica Ventricular Direita/imunologia , Autoanticorpos/imunologia , Feminino , Hirudinas/imunologia , Humanos , Masculino , Camundongos Knockout , Pessoa de Meia-Idade , Proteínas Recombinantes/imunologia , Trombina/imunologia
3.
Mol Cell Biol ; 29(22): 6046-58, 2009 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-19752190

RESUMO

The muscle LIM protein (MLP) and cofilin 2 (CFL2) are important regulators of striated myocyte function. Mutations in the corresponding genes have been directly associated with severe human cardiac and skeletal myopathies, and aberrant expression patterns have often been observed in affected muscles. Herein, we have investigated whether MLP and CFL2 are involved in common molecular mechanisms, which would promote our understanding of disease pathogenesis. We have shown for the first time, using a range of biochemical and immunohistochemical methods, that MLP binds directly to CFL2 in human cardiac and skeletal muscles. The interaction involves the inter-LIM domain, amino acids 94 to 105, of MLP and the amino-terminal domain, amino acids 1 to 105, of CFL2, which includes part of the actin depolymerization domain. The MLP/CFL2 complex is stronger in moderately acidic (pH 6.8) environments and upon CFL2 phosphorylation, while it is independent of Ca(2+) levels. This interaction has direct implications in actin cytoskeleton dynamics in regulating CFL2-dependent F-actin depolymerization, with maximal depolymerization enhancement at an MLP/CFL2 molecular ratio of 2:1. Deregulation of this interaction by intracellular pH variations, CFL2 phosphorylation, MLP or CFL2 gene mutations, or expression changes, as observed in a range of cardiac and skeletal myopathies, could impair F-actin depolymerization, leading to sarcomere dysfunction and disease.


Assuntos
Actinas/metabolismo , Cofilina 2/metabolismo , Proteínas Musculares/metabolismo , Músculo Esquelético/metabolismo , Miocárdio/metabolismo , Animais , Cálcio/metabolismo , Cardiomiopatias/metabolismo , Cardiomiopatias/patologia , Cofilina 2/química , Modelos Animais de Doenças , Humanos , Concentração de Íons de Hidrogênio , Proteínas com Domínio LIM , Camundongos , Modelos Biológicos , Modelos Moleculares , Proteínas Musculares/química , Miocárdio/patologia , Fosforilação , Ligação Proteica , Mapeamento de Interação de Proteínas , Estrutura Terciária de Proteína , Transporte Proteico , Sarcômeros/metabolismo , Frações Subcelulares/metabolismo
4.
Eur J Cell Biol ; 81(6): 363-74, 2002 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-12113477

RESUMO

Cells of the PC12 rat pheochromocytoma cell line acquire characteristics of sympathetic neurons under appropriate treatment. Stably transfected PC12 cells expressing individual alpha2-adrenergic receptor (alpha2-AR) subtypes were used to assess the role of alpha2-ARs in neuronal differentiation and to characterise the signalling pathways activated by the alpha2-AR agonist epinephrine in these cells. The effects of alpha2-AR activation were compared with the differentiating action and the signalling mechanisms of nerve growth factor (NGF). Epinephrine induced neuronal differentiation of PC12alpha2 cells through alpha2-AR activation in a subtype-dependent manner, internalization of all human alpha2-AR subtypes, and activation of mitogen-activated protein kinase (MAPK) and the serine-threonine protein kinase Akt. Epinephrine and NGF showed synergism in their differentiating effects. The MAPK kinase (MEK-1) inhibitor PD 98059 abolished the differentiating effect of epinephrine indicating that the differentiation is dependent on MAPK activation. Activating protein-1 (AP-1) DNA-binding activity was increased after epinephrine treatment in all three PC12alpha2 subtype clones. Evaluation of the potential physiological consequences of these findings requires further studies on endogenously expressed alpha2-ARs in neuronal cells.


Assuntos
Diferenciação Celular/fisiologia , Sistema Nervoso Central/embriologia , Sistema de Sinalização das MAP Quinases/fisiologia , Neurônios/metabolismo , Proteínas Serina-Treonina Quinases , Receptores Adrenérgicos alfa 2/metabolismo , Agonistas de Receptores Adrenérgicos alfa 2 , Antagonistas Adrenérgicos alfa/farmacologia , Animais , Diferenciação Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Tamanho Celular/efeitos dos fármacos , Tamanho Celular/genética , Sistema Nervoso Central/crescimento & desenvolvimento , Sistema Nervoso Central/metabolismo , Interações Medicamentosas/fisiologia , Inibidores Enzimáticos/farmacologia , Epinefrina , Vetores Genéticos , Imuno-Histoquímica , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Proteínas Quinases Ativadas por Mitógeno/efeitos dos fármacos , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Fator de Crescimento Neural/farmacologia , Neuritos/efeitos dos fármacos , Neuritos/metabolismo , Neuritos/ultraestrutura , Neurônios/citologia , Neurônios/efeitos dos fármacos , Células PC12 , Fosfatidilinositol 3-Quinases/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas/efeitos dos fármacos , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas c-akt , Ratos , Receptores Adrenérgicos alfa 2/genética , Fator de Transcrição AP-1/efeitos dos fármacos , Fator de Transcrição AP-1/metabolismo , Transfecção
5.
Am J Pathol ; 160(3): 943-52, 2002 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-11891192

RESUMO

Mice lacking the intermediate filament protein desmin demonstrate abnormal mitochondria behavior, disruption of muscle architecture, and myocardial degeneration with extensive calcium deposits and fibrosis. These abnormalities are associated with cardiomyocyte hypertrophy, cardiac chamber dilation and eventually with heart failure. In an effort to elucidate the molecular mechanisms leading to the observed pathogenesis, we have analyzed gene expression changes in cardiac tissue using differential display polymerase chain reaction and cDNA atlas array methods. The most substantial changes were found in genes coding the small extracellular matrix proteins osteopontin and decorin that are dramatically induced in the desmin-null myocardium. We further analyzed their expression pattern both at the RNA and protein levels and we compared their spatial expression with the onset of calcification. Extensive osteopontin localization is observed by immunohistochemistry in the desmin-null myocardium in areas with massive myocyte death, as well as in hypercellular regions with variable degrees of calcification and fibrosis. Osteopontin is consistently co-localized with calcified deposits, which progressively are transformed to psammoma bodies surrounded by decorin, especially in the right ventricle. These data together with the observed up-regulation of transforming growth factor-beta1 and angiotensin-converting enzyme, could explain the extensive fibrosis and dystrophic calcification observed in the heart of desmin-null mice, potentially crucial events leading to heart failure.


Assuntos
Calcinose , Cardiomiopatias/genética , Cardiomiopatias/metabolismo , Desmina/genética , Animais , Calcinose/genética , Calcinose/metabolismo , Cardiomiopatias/patologia , Decorina , Desmina/deficiência , Proteínas da Matriz Extracelular , Fibrose , Regulação da Expressão Gênica , Imuno-Histoquímica , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Osteopontina , Peptidil Dipeptidase A/biossíntese , Proteoglicanas/biossíntese , Sialoglicoproteínas/biossíntese , Fator de Crescimento Transformador beta/biossíntese
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