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Am J Pathol ; 187(3): 627-638, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28162229

RESUMO

The roles of transforming growth factor (TGF)-ß in extracellular matrix production and vascular remodeling, coupled with increased TGF-ß expression and signaling in diabetes, suggest TGF-ß as an important contributor to the microangiopathy of diabetic retinopathy and nephropathy. To investigate whether increased TGF-ß signaling could be a therapeutic target for preventing retinopathy, we used a pharmacologic approach (SM16, a selective inhibitor of the type 1 TGF-ß receptor activin receptor-like kinase 5, orally active) to inhibit the increased, but not the basal, Tgf-ß signaling in retinal vessels of diabetic rats. At the level of vascular gene expression, 3.5 months' diabetes induced minimal changes. Diabetes + SM16 for 3 weeks caused widespread changes in gene expression poised to enhance vascular inflammation, thrombosis, leakage, and wall instability; these changes were not observed in control rats given SM16. The synergy of diabetes and SM16 in altering gene expression was not observed in the lung. At the level of vascular network morphology, 7 months' diabetes induced no detectable changes. Diabetes + SM16 for 3 weeks caused instead distorted morphology and decreased density. Thus, in diabetes, retinal vessels become dependent on a small increase in TGF-ß signaling via activin receptor-like kinase 5 to maintain early integrity. The increased TGF-ß signaling may protect against rapid retinopathy progression and should not be a target of inhibitory interventions.


Assuntos
Diabetes Mellitus Experimental/metabolismo , Vasos Retinianos/metabolismo , Transdução de Sinais , Fator de Crescimento Transformador beta/metabolismo , Receptores de Ativinas/metabolismo , Animais , Apoptose/efeitos dos fármacos , Compostos Azabicíclicos/farmacologia , Glicemia/metabolismo , Peso Corporal/efeitos dos fármacos , Capilares/efeitos dos fármacos , Capilares/patologia , Quimiocina CCL2/metabolismo , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/patologia , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Hemoglobinas Glicadas/metabolismo , Masculino , Proteína Quinase 14 Ativada por Mitógeno/metabolismo , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , Vasos Retinianos/efeitos dos fármacos , Vasos Retinianos/patologia , Transdução de Sinais/efeitos dos fármacos , Fatores de Tempo
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