RESUMO
Type 2 diabetes has become a pandemic and leads to late diabetic complications of organs, including kidney and eye. Lowering hyperglycemia is the typical therapeutic goal in clinical medicine. However, hyperglycemia may only be a symptom of diabetes but not the sole cause of late diabetic complications; instead, other diabetes-related alterations could be causative. Here, we studied the role of CaM kinase II-δ (CaMKIIδ), which is known to be activated through diabetic metabolism. CaMKIIδ is expressed ubiquitously and might therefore affect several different organ systems. We crossed diabetic leptin receptor-mutant mice to mice lacking CaMKIIδ globally. Remarkably, CaMKIIδ-deficient diabetic mice did not develop hyperglycemia. As potential underlying mechanisms, we provide evidence for improved insulin sensing with increased glucose transport into skeletal muscle and also reduced hepatic glucose production. Despite normoglycemia, CaMKIIδ-deficient diabetic mice developed the full picture of diabetic nephropathy, but diabetic retinopathy was prevented. We also unmasked a retina-specific gene expression signature that might contribute to CaMKII-dependent retinal diabetic complications. These data challenge the clinical concept of normalizing hyperglycemia in diabetes as a causative treatment strategy for late diabetic complications and call for a more detailed analysis of intracellular metabolic signals in different diabetic organs.
Assuntos
Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Nefropatias Diabéticas/metabolismo , Retinopatia Diabética/metabolismo , Hiperglicemia/metabolismo , Animais , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/genética , Diabetes Mellitus Tipo 2/genética , Nefropatias Diabéticas/genética , Retinopatia Diabética/genética , Expressão Gênica , Hiperglicemia/genética , Camundongos , Camundongos Knockout , Receptores para Leptina/genética , Receptores para Leptina/metabolismoRESUMO
Amniotic membrane is applied to the diseased ocular surface to stimulate wound healing and tissue repair, because it releases supportive growth factors and cytokines. These effects fade within about a week after application, necessitating repeated application. Generally, amniotic membrane is fixed with sutures to the ocular surface, but surgical intervention at the inflamed or diseased site can be detrimental. Therefore, we have developed a system for the mounting of amniotic membrane between two rings for application to a diseased ocular surface without surgical intervention (sutureless amniotic membrane transplantation). With this system, AmnioClip, amniotic membrane can be applied like a large contact lens. First prototypes were tested in an experiment on oneself for wearing comfort. The final system was tested on 7 patients in a pilot study. A possible influence of the ring system on the biological effects of amniotic membrane was analyzed by histochemistry and by analyzing the expression of vascular endothelial growth factor-A (VEGF-A), hepatocyte growth factor (HGF), fibroblast growth factor 2 (FGF 2) and pigment epithelium-derived factor (PEDF) from amniotic membranes before and after therapeutic application. The final product, AmnioClip, showed good tolerance and did not impair the biological effects of amniotic membrane. VEGF-A and PEDF mRNA was expressed in amniotic membrane after storage and mounting before transplantation, but was undetectable after a 7-day application period. Consequently, transplantation of amniotic membranes with AmnioClip provides a sutureless and hence improved therapeutic strategy for corneal surface disorders.Trial Registration:ClinicalTrials.gov NCT02168790
Assuntos
Curativos Biológicos , Córnea/patologia , Doenças da Córnea/terapia , Epitélio Corneano/patologia , Procedimentos Cirúrgicos Oftalmológicos/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Âmnio/metabolismo , Âmnio/cirurgia , Biomarcadores/metabolismo , Doenças da Córnea/patologia , Desenho de Equipamento , Proteínas do Olho/genética , Proteínas do Olho/metabolismo , Feminino , Fator 2 de Crescimento de Fibroblastos/genética , Fator 2 de Crescimento de Fibroblastos/metabolismo , Expressão Gênica , Fator de Crescimento de Hepatócito/genética , Fator de Crescimento de Hepatócito/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Crescimento Neural/genética , Fatores de Crescimento Neural/metabolismo , Procedimentos Cirúrgicos Oftalmológicos/instrumentação , Projetos Piloto , Serpinas/genética , Serpinas/metabolismo , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
CaMKII was suggested to mediate ischemic myocardial injury and adverse cardiac remodeling. Here, we investigated the roles of different CaMKII isoforms and splice variants in ischemia/reperfusion (I/R) injury by the use of new genetic CaMKII mouse models. Although CaMKIIδC was upregulated 1 day after I/R injury, cardiac damage 1 day after I/R was neither affected in CaMKIIδ-deficient mice, CaMKIIδ-deficient mice in which the splice variants CaMKIIδB and C were re-expressed, nor in cardiomyocyte-specific CaMKIIδ/γ double knockout mice (DKO). In contrast, 5 weeks after I/R, DKO mice were protected against extensive scar formation and cardiac dysfunction, which was associated with reduced leukocyte infiltration and attenuated expression of members of the chemokine (C-C motif) ligand family, in particular CCL3 (macrophage inflammatory protein-1α, MIP-1α). Intriguingly, CaMKII was sufficient and required to induce CCL3 expression in isolated cardiomyocytes, indicating a cardiomyocyte autonomous effect. We propose that CaMKII-dependent chemoattractant signaling explains the effects on post-I/R remodeling. Taken together, we demonstrate that CaMKII is not critically involved in acute I/R-induced damage but in the process of post-infarct remodeling and inflammatory processes.
