Correlation of diacylglycerol level and protein kinase C activity in rat retina to retinal circulation

Shiba, Teruo; Inoguchi, Toyoshi; Sportsman, J. Richard; Heath, William F.; Bursell, Sven–Erik; King, George L.

doi:10.1152/ajpendo.1993.265.5.e783

Cited by 199 publications

(248 citation statements)

References 24 publications

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“…In agreement, in ocular tissues of diabetic rats increased concentrations of IR-ET-1 have been shown [43]. This alteration, partially reversed by insulin treatment, could be due to hyperglycaemia that activates protein kinase C, initiating a pathway competent for increased ET-1 gene expression [44].…”

Section: Discussionsupporting

confidence: 57%

Changes in the density and localisation of endothelin receptors in the early stages of rat diabetic retinopathy and the effect of insulin treatment

et al. 2000

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The endothelins (ETs) are a family of 2500 M r peptides with three distinct isoforms, endothelin-1, ±2 and ±3 (ET-1, ET-2 and ET-3) [1,2]. ET-1 is a potent vasoconstrictor produced by endothelial cells that also induces mitogenesis in vascular smooth muscle cells [1,3]. Two major types of ET receptors, termed endothelin receptor type A (ETA) and endothelin receptor type B (ETB) have been identified, cloned and sequenced in mammals [4,5]. The ETA receptor mediates most of the vasoconstrictor action of ET-1 and has selective affinity for . The ETB receptor has equal affinities for all ET isoforms and has been shown to release endothelium-derived nitric Abstract Aims/hypothesis. The endothelin system (ET system) has been implicated in the retinal blood flow abnormalities that precede the onset of diabetic retinopathy. This study was undertaken to assess whether the density and localisation of both the immunoreactive endothelin-1 and endothelin receptors in rat retina change in the early stages of diabetes and the insulin treatment would affect those changes. Methods. Untreated streptozotocin-diabetic, insulintreated streptozotocin-diabetic and age-matched control rats were killed 15, 45 and 90 days after the induction of diabetes. Binding assays were used to determine the density and proportion of endothelin receptors in neural retinal membranes. Localisation of endothelin receptors and immunoreactive endothelin-1 were analysed by microautoradiography and immunohistochemistry, respectively. Results. Fifteen days after the induction of diabetes, the neural retinal membranes of untreated streptozotocin-diabetic rats showed a statistically significant decrease in the density of both endothelin receptor subtypes when compared with age-matched control rats. At 90 days, however, the density of endothelin receptors type B was statistically significantly higher than that of control rats, and the innermost layers of the diabetic retina also showed an increase of both endothelin receptor type B receptor and immunoreactive endothelin-1 signal. Insulin treatment during 90 days up-regulated endothelin receptor type A in neural retinal membranes and in the innermost layers of the retina when compared with control retinas. Conclusion/interpretation. These results show that the endothelin system is altered in both vascular and neuronal components of the retina in early diabetic retinopathy. The up-regulation of endothelin receptor type A induced by insulin treatment suggests that insulin might be involved in retinal microangiopathy. [Diabetologia (2000) 43: 773±785]

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Section: Discussionsupporting

confidence: 57%

Changes in the density and localisation of endothelin receptors in the early stages of rat diabetic retinopathy and the effect of insulin treatment

et al. 2000

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“…In addition, intravitreal injections of endothelin-1 or phorbol dibutyrate (an activator of PKC) rapidly induced retinal arteriole constriction and prolonged MCT, which mimicked diabetes [31,32]. In contrast, intravitreal injection of angiotensin II, at doses up to 10 −3 mol/l, did not increase MCT or inhibit RBF (data not shown).…”

Section: Discussionmentioning

confidence: 99%

“…In this report, we show that the AT 1 receptor antagonism normalized retinal DAG levels in diabetes. Since RBF is regulated by resistance arteriole and capillary pericytes [31], we propose that AngII/AT 1 effects on reti- nal haemodynamics are mediated by the up-regulation factors, such as endothelin-1 and/or DAG/PKC pathways, which induce sustained microvascular constriction [31,32]. This conclusion is consistent with the results showing that treatment of DM rats with either captopril or candesartan normalized MCT and RBF without affecting primary retinal artery or vein diameters.…”

Section: Discussionmentioning

confidence: 99%

“…It has also been shown that both retinal microcapillary endothelial cells and pericytes express angiotensin AT 1 receptors [40,41]. Therefore increased production of angiotensin II within the retina might act in an autocrine or paracrine manner to increase factors, such as DAG, which leads to arteriole vasoconstriction [32]. Alternatively, diabetes could decrease activities of retinal-derived relating factors [42,43], resulting in the enhanced vasoconstriction by normal levels of angiotensin II-activation of AT 1 receptor activity.…”

Section: Discussionmentioning

confidence: 99%

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Angiotensin AT 1 receptor antagonism normalizes retinal blood flow and acetylcholine-induced vasodiliation in normotensive diabetic rats

et al. 2004

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Aims/hypothesis. The renin angiotensin system is emerging as a potential therapeutic target for diabetic retinopathy. This study examines the effects of angiotensin-converting-enzyme inhibition by captopril and angiotensin AT 1 receptor antagonism using candesartan-cilexetil on retinal blood flow and acetylcholinestimulated vasodilatation in normotensive diabetic rats. Methods. Non-diabetic or streptozotocin-induced diabetic rats were treated for 2 weeks with captopril (100 mg/kg/day) or candesartan cilexetil (2 mg/kg/day). Retinal haemodynamics were measured using video fluorescein angiography. Effects of exogenous acetylcholine on retinal haemodynamics were examined following intravitreal injection. Total retinal diacylglycerol was labelled using diacylglycerol kinase, separated by thin-layer chromatography, and quantified using autoradiography. Results. Diabetic rats had prolonged retinal mean circulation time and decreased retinal blood flow compared with non-diabetic rats. Treatment of diabetic rats with either captopril or candesartan blocked the development of these blood flow abnormalities. Intraviteral injection of acetylcholine (10 −5 mol/l) in non-diabetic rats increased retinal blood flow by 53.9±22.0% relative to baseline whereas this response to acetylcholine was blunted in diabetic rats (4.4±19.6%, p<0.001). Candesartan treatment of diabetic rats restored the acetylcholine-stimulated retinal blood flow response to 60.0±18.7% compared with a 56.2+20.1% response in candesartan-treated non-diabetic rats. Total retinal diacylglycerol levels were increased in diabetic rats (3.75±0.98 nmol/mg, p<0.05) compared with non-diabetic rats (2.13±0.25 nmol/mg) and candesartan-treatment of diabetic rats normalized diacylglycerol levels (2.10±0.25 nmol/mg, p<0.05). Conclusion/interpretation. This report provides evidence that angiotensin-converting enzyme inhibition and AT 1 receptor antagonism ameliorates retinal haemodynamic dysfunctions in normotensive diabetic rats. [Diabetologia (2004) 47:113-123]

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“…Pathological activation of PKC has been previously reported in the aorta, heart (10), kidney (11), and retina (12,13) in diabetic animals. The activation of PKC was also found to be closely related to the development of complications of diabetes such as atherosclerosis, retinopathy, and nephropathy (14,15).…”

mentioning

confidence: 80%

Phosphorylation of Pleckstrin Increases Proinflammatory Cytokine Secretion by Mononuclear Phagocytes in Diabetes Mellitus

Ding

Kantarcı

Badwey

et al. 2007

The Journal of Immunology

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The protein kinase C (PKC) family of intracellular enzymes plays a crucial role in signal transduction for a variety of cellular responses of mononuclear phagocytes including phagocytosis, oxidative burst, and secretion. Alterations in the activation pathways of PKC in a variety of cell types have been implicated in the pathogenesis of the complications of diabetes. In this study, we investigated the consequences of PKC activation by evaluating endogenous phosphorylation of PKC substrates with a phosphospecific PKC substrate Ab (pPKC(s)). Phosphorylation of a 40-kDa protein was significantly increased in mononuclear phagocytes from diabetics. Phosphorylation of this protein is downstream of PKC activation and its phosphorylated form was found to be associated with the membrane. Mass spectrometry analysis, immunoprecipitation, and immunoblotting experiments revealed that this 40-kDa protein is pleckstrin. We then investigated the phosphorylation and translocation of pleckstrin in response to the activation of receptor for advanced glycation end products (RAGE). The results suggest that pleckstrin is involved in RAGE signaling and advanced glycation end product (AGE)-elicited mononuclear phagocyte dysfunction. Suppression of pleckstrin expression with RNA interference silencing revealed that phosphorylation of pleckstrin is an important intermediate in the secretion and activation pathways of proinflammatory cytokines (TNF-α and IL-1β) induced by RAGE activation. In summary, this study demonstrates that phosphorylation of pleckstrin is up-regulated in diabetic mononuclear phagocytes. The phosphorylation is in part due to the activation of PKC through RAGE binding, and pleckstrin is a critical molecule for proinflammatory cytokine secretion in response to elevated AGE in diabetes.

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Correlation of diacylglycerol level and protein kinase C activity in rat retina to retinal circulation

Cited by 199 publications

References 24 publications

Changes in the density and localisation of endothelin receptors in the early stages of rat diabetic retinopathy and the effect of insulin treatment

Changes in the density and localisation of endothelin receptors in the early stages of rat diabetic retinopathy and the effect of insulin treatment

Angiotensin AT 1 receptor antagonism normalizes retinal blood flow and acetylcholine-induced vasodiliation in normotensive diabetic rats

Phosphorylation of Pleckstrin Increases Proinflammatory Cytokine Secretion by Mononuclear Phagocytes in Diabetes Mellitus

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