Heme oxygenase in the retina in diabetes

Cukiernik, Mark; Mukherjee, Shankar; Downey, Dónal B.; Chakabarti, Subrata

doi:10.1076/ceyr.27.5.301.17227

Cited by 37 publications

(30 citation statements)

References 51 publications

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“…Haemoxygenase-1 levels in diabetic retina Consistent with previous reports [25,26], this study identified differences in the pattern of retinal levels of the oxidative stress marker haemoxygenase-1 when diabetic retinas were compared with controls (p < 0.001). As shown in Fig.…”

Section: Resultssupporting

confidence: 91%

“…Pyridoxamine also prevents ALE formation in diabetic and obese rats [36,37] through cleavage of alpha-dicarbonyl intermediates in glycoxidation and lipoxidation reactions [38]. It also effectively reduced upregulation of retinal haemoxygenase-1, which is significant as this enzyme has been previously used as a reliable marker of oxidative stress in diabetic retinopathy [25,26]. It is known that AGE/ALE adducts are linked to generation of reactive oxygen species in the central nervous system [39].…”

Section: Discussionmentioning

confidence: 99%

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Müller glial dysfunction during diabetic retinopathy in rats is linked to accumulation of advanced glycation end-products and advanced lipoxidation end-products

et al. 2010

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Aims/hypothesis The impact of AGEs and advanced lipoxidation end-products (ALEs) on neuronal and Müller glial dysfunction in the diabetic retina is not well understood. We therefore sought to identify dysfunction of the retinal Müller glia during diabetes and to determine whether inhibition of AGEs/ALEs can prevent it. Methods Sprague-Dawley rats were divided into three groups: (1) non-diabetic; (2) untreated streptozotocininduced diabetic; and (3) diabetic treated with the AGE/ ALE inhibitor pyridoxamine for the duration of diabetes. Rats were killed and their retinas were evaluated for neuroglial pathology. Results AGEs and ALEs accumulated at higher levels in diabetic retinas than in controls (p<0.001). AGE/ALE immunoreactivity was significantly diminished by pyridoxamine treatment of diabetic rats. Diabetes was also associated with the up-regulation of the oxidative stress marker haemoxygenase-1 and the induction of glial fibrillary acidic protein production in Müller glia (p<0.001). Pyridoxamine treatment of diabetic rats had a significant beneficial effect on both variables (p < 0.001). Diabetes also significantly altered the normal localisation of the potassium inwardly rectifying channel Kir4.1 and the water channel aquaporin 4 to the Müller glia end-feet interacting with retinal capillaries. These abnormalities were prevented by pyridoxamine treatment. Conclusions/interpretation While it is established that AGE/ALE formation in the retina during diabetes is linked to microvascular dysfunction, this study suggests that these pathogenic adducts also play a role in Müller glial dysfunction.

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Section: Resultssupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Müller glial dysfunction during diabetic retinopathy in rats is linked to accumulation of advanced glycation end-products and advanced lipoxidation end-products

et al. 2010

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“…We have previously shown that HO-1 is upregulated in monocytes from patients with type 2 diabetes (Avogaro et al, 2003). Experimentally, diabetes leads to upregulation of HO-1 in retinal vessels (Cukiernik et al, 2003); however, data from other groups indicate that HO activity is decreased in aortas from diabetic rats compared with control (Quan et al, 2004). Abraham et al found that high glucose inhibited HO activity and decreased HO-1 protein in endothelial cells .…”

Section: Discussionmentioning

confidence: 97%

Heme oxygenase-1 is an important modulator in limiting glucose-induced apoptosis in human umbilical vein endothelial cells

Iori¹,

Pagnin²,

Gallo³

et al. 2008

Life Sciences

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“…An overwhelming body of evidence indicates that the heme-HO system is intrinsically involved in the regulation of many physiological and pathophysiological processes, including diabetes (27,28). Hyperglycemia may also enhance retinal ROS production causing cell damage and death.…”

Section: Discussionmentioning

confidence: 99%

Selective Regulation of Heme Oxygenase-1 Expression and Function by Insulin through IRS1/Phosphoinositide 3-Kinase/Akt-2 Pathway

Geraldes

Yagi

Ohshiro

et al. 2008

Journal of Biological Chemistry

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Oxidative stress, as a result of hyperglycemia and diabetes, has been postulated to be a major metabolic abnormality causing a variety of cellular dysfunctions and vascular pathologies (1-3). Increases in oxidative stress in patients who have diabetes with poor glycemic control or insulin resistance may result from enhanced production of reactive oxygen species (ROS) 3 because of metabolism of metabolites such as elevated glucose and free fatty acid levels in excess of endogenous antioxidant defense (4 -6). Large clinical studies such as Diabetes Complications and Control Trial and the Epidemiology of Diabetes Interventions and Complications trials have clearly identified hyperglycemia as one of the main initiating factors of diabetic complications that can be mitigated by insulin treatment in type 1 diabetic patients (7,8). One of the earliest and most specific histopathological findings associated with hyperglycemia and diabetic retinopathy is the selective loss of retinal capillary pericytes, probably because of apoptosis (9). Many studies have proposed that oxidative stress via elevation of glucose levels is one of the potential triggers of the increased rate of pericyte apoptosis (10, 11). Antioxidant treatments have been reported to ameliorate diabetic retinopathy by preserving retinal vascular pericytes in rodent models of diabetes (12). However, in large clinical studies, including the Heart Outcomes Prevention Study, antioxidant treatments such as vitamins C and E did not provide substantial improvement of microvascular or cardiovascular damage in individuals who had diabetes for several years (13). Thus, it is possible that in addition to normalizing hyperglycemia, insulin may directly affect the endogenous antioxidant defense to neutralize the intracellular elevation of oxidants induced by the metabolism of elevated levels of glucose or free fatty acids.Heme oxygenase (HO) plays an important key role in regulating the intracellular heme level by catalyzing the initial and rate-limiting step of heme degradation, in which oxidative cleavage of the porphyrin ring results in formation of biliverdin, CO, and free iron (14,15). A number of studies have demon-

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Heme oxygenase in the retina in diabetes

Abstract: The present data suggests that the HO system is up-regulated in short term diabetes leading to HO and NO interactions which may modulate vascular function in the retina.

Cited by 37 publications

References 51 publications

Müller glial dysfunction during diabetic retinopathy in rats is linked to accumulation of advanced glycation end-products and advanced lipoxidation end-products

Müller glial dysfunction during diabetic retinopathy in rats is linked to accumulation of advanced glycation end-products and advanced lipoxidation end-products

Heme oxygenase-1 is an important modulator in limiting glucose-induced apoptosis in human umbilical vein endothelial cells

Selective Regulation of Heme Oxygenase-1 Expression and Function by Insulin through IRS1/Phosphoinositide 3-Kinase/Akt-2 Pathway

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