RESUMO
Diabetes and hypertension are complex pathologies with increasing prevalence nowadays. Their interconnected pathways are frequently manifested in retinopathies. Severe retinal consequences and their tight connections as well as their possible treatments are particularly important to retinal research. In the present, work we induced diabetes with streptozotocin in spontaneously hypertensive rats and treated them either with PACAP or olaparib and alternatively with both agents. Morphological and immunohistochemical analyses were carried out to describe cell-specific changes during pathologies and after different treatments. Diabetes and hypertension caused massive structural and cellular changes especially when they were elicited together. Hypertension was crucial in the formation of ONL and OPL damage while diabetes caused significant differences in retinal thickness, OPL thickness and in the cell number of the GCL. In diabetes, double neuroprotective treatment ameliorated changes of calbindin-positive cells, rod bipolar cells and dopaminergic amacrine cells. Double treatment was curative in hypertensive diabetic rat retinas, especially in the case of rod bipolar and parvalbumin-positive cells compared to untreated or single-treated retinas. Our results highlighted the promising therapeutic benefits of olaparib and PACAP in these severe metabolic retinal disorders.
Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Retinopatia Diabética/tratamento farmacológico , Retinopatia Hipertensiva/tratamento farmacológico , Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Células Amácrinas/efeitos dos fármacos , Animais , Calbindinas/genética , Linhagem da Célula/efeitos dos fármacos , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/patologia , Retinopatia Diabética/genética , Retinopatia Diabética/patologia , Modelos Animais de Doenças , Humanos , Retinopatia Hipertensiva/genética , Retinopatia Hipertensiva/patologia , Ftalazinas/farmacologia , Piperazinas/farmacologia , Ratos , Ratos Endogâmicos SHR/genética , Células Bipolares da Retina/efeitos dos fármacosRESUMO
Severe hypertension destroys eyesight. The RAS (renin-angiotensin system) may contribute to this. This study relied on an established angiotensin, AngII (angiotensin II)-elevated dTGR (double-transgenic rat) model and same-background SD (Sprague-Dawley) rat controls. In dTGRs, plasma levels of AngII were increased. We determined the general retinal phenotype and observed degeneration of ganglion cells that we defined as vascular degeneration. We also inspected relevant gene expression and lastly observed alterations in the outer blood-retinal barrier. We found that both scotopic a-wave and b-wave as well as oscillatory potential amplitude were significantly decreased in dTGRs, compared with SD rat controls. However, the b/a-wave ratio remained unchanged. Fluorescence angiography of the peripheral retina indicated that exudates, or fluorescein leakage, from peripheral vessels were increased in dTGRs compared with controls. Immunohistological analysis of blood vessels in retina whole-mount preparations showed structural alterations in the retina of dTGRs. We then determined the general retinal phenotype. We observed the degeneration of ganglion cells, defined vascular degenerations and finally found differential expression of RAS-related genes and angiogenic genes. We found the expression of both human angiotensinogen and human renin in the hypertensive retina. Although the renin gene expression was not altered, the AngII levels in the retina were increased 4-fold in the dTGR retina compared with that in SD rats, a finding with mechanistic implications. We suggest that alterations in the outer blood-retinal barrier could foster an area of visual-related research based on our findings. Finally, we introduce the dTGR model of retinal disease.
Assuntos
Retinopatia Hipertensiva/fisiopatologia , Sistema Renina-Angiotensina/genética , Angiotensina II/metabolismo , Angiotensinogênio/genética , Animais , Pressão Sanguínea/fisiologia , Modelos Animais de Doenças , Retinopatia Hipertensiva/genética , Masculino , Ratos Transgênicos , Renina/metabolismoRESUMO
Even in the new millennium, arterial hypertension remains a serious condition, with considerable morbidity and mortality worldwide. Crucial in managing the disease is not only lowering arterial blood pressure but also preventing or treating the typical end-organ damage caused by long-lasting and inadequately treated hypertension. In the past decade, it has been shown that microRNAs (miRs) are involved in several hypertension-related pathologies, such as cardiac hypertrophy and fibrosis, hypertensive heart failure, renal fibrosis, kidney failure, and, to a lesser extent, eye disease and hemorrhagic stroke. Whereas others extensively reviewed the role of miRs in atherosclerosis and vascular disease, this review focuses on their role in target organ damage during arterial hypertension. We emphasize the involvement of miRs in pathological end-organ remodeling processes and try to demonstrate some common miR signatures in distinct end organs. Hence, we aimed to provide proof of arterial hypertension being a systemic disease, similar to diabetes mellitus or metabolic syndrome. Furthermore, miRs that act on one particular process in different end organs are interesting therapeutic targets. Some future perspectives in miR research are highlighted with respect to novel therapeutic strategies in the cardiovascular field.
