RESUMO
[Figure: see text].
Assuntos
Antígeno CD146 , Glomerulonefrite , Animais , Antígeno CD146/genética , Antígeno CD146/metabolismo , Modelos Animais de Doenças , Descoberta de Drogas , Células Endoteliais/metabolismo , Fibrose/metabolismo , Fibrose/prevenção & controle , Técnicas de Inativação de Genes/métodos , Glomerulonefrite/imunologia , Glomerulonefrite/metabolismo , Glomerulonefrite/terapia , Inflamação/metabolismo , Inflamação/prevenção & controle , Junções Intercelulares/imunologia , Glomérulos Renais/imunologia , Camundongos , Regulação para CimaRESUMO
Background: O-GlcNAcylation is a posttranslational modification associated with various physiological and pathophysiological processes including diabetes, cancer, neurodegeneration and inflammation. However, the biological mechanisms underlying the role of specific O-GlcNAc sites and their link to phenotypes remain largely unexplored due to lack of suitable in vivo models. TGF-ß activated kinase-1 binding protein-1 (TAB1) is a scaffolding protein required for TGF-ß activated kinase-1 (TAK1) mediated signalling. A single O-GlcNAc site has been identified on human TAB1 that modulates TAK1-mediated cytokine release in cells. Methods: Here, we report the generation of the Tab1 S393A mouse model using a constitutive knock-in strategy. The Tab1 S393A mice carry a Ser393Ala (S393A) mutation that leads to loss of O-GlcNAcylation site on TAB1. Results: We did not observe any obvious phenotype in Tab1 S393A mice. Loss of O-GlcNAcylation on TAB1 has no consequences on TAB1 protein level or on TAB1-TAK1 interaction. Conclusions: The homozygous Tab1 S393A mice are viable and develop with no obvious abnormalities, providing a powerful tool to further investigate the role of O-GlcNAc on TAB1 in the inflammatory response in the context of a whole organism.
RESUMO
BACKGROUND: Achondroplasia is a rare genetic disease is characterized by abnormal bone development and early obesity. While the bone aspect of the disease has been thoroughly studied, early obesity affecting approximately 50% of them during childhood has been somewhat neglected. It nevertheless represents a major health problem in these patients, and is associated to life-threatening complications including increasing risk of cardiovascular pathologies. We have thus decided to study obesity in patients and to use the mouse model to evaluate if soluble FGFR3 therapy, an innovative treatment approach for achondroplasia, could also impact the development of this significant complication. METHODS AND FINDINGS: To achieve this, we have first fully characterized the metabolic deregulations in these patients by conducting a longitudinal retrospective study, in children with achondroplasia Anthropometric, densitometric measures as well as several blood parameters were recorded and compared between three age groups ranging from [0-3], [4-8] and [9-18] years old. Our results show unexpected results with the development of an atypical obesity with preferential fat deposition in the abdomen that is remarkably not associated with classical complications of obesity such as diabetes or hypercholosterolemia. Because it is not associated with diabetes, the atypical obesity has not been studied in the past even though it is recognized as a real problem in these patients. These results were validated in a murine model of achondroplasia (Fgfr3ach/+) where similar visceral adiposity was observed. Unexpected alterations in glucose metabolism were highlighted during high-fat diet. Glucose, insulin or lipid levels remained low, without the development of diabetes. Very interestingly, in achondroplasia mice treated with soluble FGFR3 during the growth period (from D3 to D22), the development of these metabolic deregulations was prevented in adult animals (between 4 and 14 weeks of age). The lean-over-fat tissues ratio was restored and glucose metabolism showed normal levels. Treating Fgfr3ach/+ mice with soluble FGFR3 during the growth period, prevented the development of these metabolic deregulations in adult animals and restored lean-over-fat tissues ratio as well as glucose metabolism in adult animals. CONCLUSION: This study demonstrate that achondroplasia patients develop an atypical obesity with preferential abdominal obesity not associated with classical complications. These results suggest that achondroplasia induces an uncommon metabolism of energy, directly linked to the FGFR3 mutation. These data strongly suggest that this common complication of achondroplasia should be included in the clinical management of patients. In this context, sFGFR3 proved to be a promising treatment for achondroplasia by normalizing the biology at different levels, not only restoring bone growth but also preventing the atypical visceral obesity and some metabolic deregulations.
Assuntos
Acondroplasia/complicações , Acondroplasia/genética , Obesidade/etiologia , Obesidade/prevenção & controle , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/uso terapêutico , Acondroplasia/diagnóstico , Acondroplasia/tratamento farmacológico , Adolescente , Animais , Biomarcadores , Glicemia , Criança , Pré-Escolar , Modelos Animais de Doenças , Feminino , Humanos , Lactente , Recém-Nascido , Insulina/metabolismo , Metabolismo dos Lipídeos , Masculino , Células-Tronco Mesenquimais/metabolismo , Camundongos , Camundongos Transgênicos , Receptor Tipo 3 de Fator de Crescimento de Fibroblastos/farmacologia , Prevenção SecundáriaRESUMO
The main hallmark of chronic kidney disease (CKD) is excessive inflammation leading to interstitial tissue fibrosis. It has been recently reported that NOV/CCN3 could be involved in kidney damage but its role in the progression of nephropathies is poorly known. NOV/CCN3 is a secreted multifunctional protein belonging to the CCN family involved in different physiological and pathological processes such as angiogenesis, inflammation and cancers. The purpose of our study was to determine the role of NOV/CCN3 in renal inflammation and fibrosis related to primitive tubulointerstitial injury. After unilateral ureteral obstruction (UUO), renal histology and real-time PCR were performed in NOV/CCN3-/- and wild type mice. NOV/CCN3 mRNA expression was increased in the obstructed kidneys in the early stages of the obstructive nephropathy. Interestingly, plasmatic levels of NOV/CCN3 were strongly induced after 7 days of UUO and the injection of recombinant NOV/CCN3 protein in healthy mice significantly increased CCL2 mRNA levels. Furthermore, after 7 days of UUO NOV/CCN3-/- mice displayed reduced proinflammatory cytokines and adhesion markers expression leading to restricted accumulation of interstitial monocytes, in comparison with their wild type littermates. Consequently, in NOV/CCN3-/- mice interstitial renal fibrosis was blunted after 15 days of UUO. In agreement with our experimental data, NOV/CCN3 expression was highly increased in biopsies of patients with tubulointerstitial nephritis. Thus, the inhibition of NOV/CCN3 may represent a novel target for the progression of renal diseases.