Aldose reductase localization in dog retinal mural cells

Akagi, Yoshio; Terubayashi, H; Millen, Jane; Kador, Peter F.; Kinoshita, Jin H.

doi:10.3109/02713688609029241

Cited by 54 publications

(50 citation statements)

References 7 publications

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“…Aldose reductase immunoreactivity has been reported in retinal pericytes and endothelial cells of the BB rat (14) but not detected in these cell types in other rat studies (13). The methods used for tissue preparation appear to affect aldose reductase immunoreactivity (18). We could not detect signal in the capillary network prepared by trypsin digestion of retinas fixed in 10% formalin for 24 -96 h, but we did in capillaries isolated from fresh retinas and fixed in formalin for 15 min (Fig.…”

Section: Resultscontrasting

confidence: 43%

“…Aldose reductase is present in human retinal endothelial cells. Human retinal pericytes are known to contain aldose reductase (18), but endothelial cells have been reported not to show immunoreactivity (16,18). The retinal tissue examined in the above studies was fixed in 4% paraformaldehyde for at least 8 h (16,18).…”

Section: Resultsmentioning

confidence: 99%

“…In rats with 2.5 months of streptozotocin-induced diabetes, retinal neurons undergoing apoptosis were positive for aldose reductase, and sorbinil prevented both neuronal apoptosis and Mü ller cell reactivity (12). Since neuroglial changes may cause vascular changes (17), and there is agreement that at least the pericytes of retinal capillaries contain aldose reductase (14,18), the question arose as to whether inhibition of the polyol pathway would also prevent the vascular abnormal-ities spanning all the way to the development of acellular capillaries in diabetic rats. We found no studies addressing this question comprehensively in diabetic rats, despite the fact that the diabetic rat is the most widely used animal model for the study of diabetic retinopathy.…”

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confidence: 99%

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Studies of Rat and Human Retinas Predict a Role for the Polyol Pathway in Human Diabetic Retinopathy

et al. 2004

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The polyol (sorbitol) pathway of glucose metabolism is activated in many cell types when intracellular glucose concentrations are high, and it can generate cellular stress through several mechanisms. The role of the polyol pathway in the pathogenesis of diabetic retinopathy has remained uncertain, in part because it has been examined preferentially in galactose-induced retinopathy and in part because inhibition studies may not have achieved full blockade of the pathway. Having observed that the streptozotocin-induced diabetic rat accurately models many cellular processes characteristic of human diabetic retinopathy, we tested in the diabetic rat if documented inhibition of the polyol pathway prevents a sequence of retinal vascular abnormalities also present in human diabetes. An inhibitor of aldose reductase, the rate-limiting enzyme in the pathway, prevented the early activation of complement in the wall of retinal vessels and the decreased levels of complement inhibitors in diabetic rats, as well as the later apoptosis of vascular pericytes and endothelial cells and the development of acellular capillaries. Both rat and human retinal endothelial cells showed aldose reductase immunoreactivity, and human retinas exposed to high glucose in organ culture increased the production of sorbitol by a degree similar to that observed in the rat. Excess aldose reductase activity can be a mechanism for human diabetic retinopathy. Diabetes 53: 2404 -2411, 2004 M ost cells of the retina are affected by the metabolic abnormalities of diabetes (1), but the sight-threatening manifestations of diabetic retinopathy are ultimately attributable to capillary damage. Abnormal permeability of barrier capillaries can cause macular edema, and capillary closure causes ischemia and unregulated angiogenesis (2). The current means to maintain a normal metabolic status in diabetic patients are imperfect, and they are successful in only a fraction of patients. It would thus be desirable to complement antidiabetic therapy with drugs that target processes specific to the complications of diabetes.The polyol pathway of glucose metabolism becomes active when intracellular glucose levels are elevated (3,4). Aldose reductase, the first and rate-limiting enzyme in the pathway, reduces glucose to sorbitol using NADPH as a cofactor; sorbitol is then metabolized to fructose by sorbitol dehydrogenase, which uses NAD ϩ as a cofactor. The polyol pathway is both a "dream" and a "dread" target when devising strategies to prevent diabetic retinopathy. The pathway is a dream target because its activation is immediately linked to hyperglycemia, generates various types of cellular stress (4 -6), and occurs prominently in the tissues that develop complications (3-6), thus promising returns beyond retinopathy. In addition, polymorphisms of the aldose reductase gene may help predict individual susceptibility to retinopathy and other microvascular complications (7), and the enzymatic function of aldose reductase can be specifically inhibited (4) with the expecta...

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Section: Resultscontrasting

confidence: 43%

Section: Resultsmentioning

confidence: 99%

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confidence: 99%

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Studies of Rat and Human Retinas Predict a Role for the Polyol Pathway in Human Diabetic Retinopathy

et al. 2004

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“…Of note, aldose reductase activation was found to also be the mechanism for the oxidative and nitrosative stress imposed by high glucose on retinal endothelial cells (from bovine retina) (25). Aldose reductase may also be an important relay to glucose toxicity in the human retina, which 1) shows the presence of aldose reductase in neural, glial, and vascular cells (1,26,27); 2) activates the polyol pathway in response to high glucose levels in vitro (1); and 3) manifests in diabetes the very same abnormalities-neuronal apoptosis (28), glial reactivity (29), and complement activation (30)-that in the retina of diabetic rats are prevented by ARIs. However, the causal link between polyol pathway activation and tissue pathology has not yet been demonstrated in humans, and only potent and safe ARIs will permit us to eventually affirm or reject the link all the way to microangiopathy.…”

Section: Discussionmentioning

confidence: 99%

A Selective Aldose Reductase Inhibitor of a New Structural Class Prevents or Reverses Early Retinal Abnormalities in Experimental Diabetic Retinopathy

et al. 2006

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Previously studied inhibitors of aldose reductase were largely from two chemical classes, spirosuccinamide/hydantoins and carboxylic acids. Each class has its own drawbacks regarding selectivity, in vivo potency, and human safety; as a result, the pathogenic role of aldose reductase in diabetic retinopathy remains controversial. ARI-809 is a recently discovered aldose reductase inhibitor (ARI) of a new structural class, pyridazinones, and has high selectivity for aldose versus aldehyde reductase. To further test the possible pathogenic role of aldose reductase in the development of diabetic retinopathy, we examined the retinal effects of this structurally novel and highly selective ARI in insulinized streptozotocin-induced diabetic rats. ARI-809 treatment was initiated 1 month after diabetes induction and continued for 3 months at a dose that inhibited the polyol pathway in the retina of diabetic rats to a similar extent as sorbinil, a poorly selective hydantoin ARI previously shown to prevent retinopathy in this model. ARI-809 improved survival, inhibited cataract development, normalized retinal sorbitol and fructose, and protected the retina from abnormalities that also occur in human diabetes: neuronal apoptosis, glial reactivity, and complement deposition. Because ARI-809 is a novel chemotype highly selective for aldose reductase, these results support the notion that aldose reductase is the key relay that converts hyperglycemia into glucose toxicity in neural and glial cell types in the retina. Diabetes 55:2757-2762, 2006

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“…In particular, the polyol pathway is correlated strongly with oxidative stress, activation of PKC, and accumulation of AGEs that lead to induction of vascular endothelial growth factor (VEGF). A key enzyme in the polyol pathway, aldose reductase (AR), is found in the retina and lens (Akagi et al, 1983;Kern & Engerman, 1981). AR inhibitors (ARIs) slowed thickening of the basement membrane of the retinal capillaries and progression of diabetic cataract in experimental studies (Hu et al, 1983;Robison et al, 1983).…”

Section: Introductionmentioning

confidence: 99%