Acute onset of diabetic pathological changes in transgenic mice with human aldose reductase cDNA

Yamaoka, Takashi; Nishimura, Chihiro; Yamashita, K.; Itakura, Masaru; Yamada, Taketo; Fujimoto, J.; Kokai, Yasuo

doi:10.1007/s001250050278

Cited by 17 publications

(10 citation statements)

References 13 publications

(18 reference statements)

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“…Genetic modulation of AR alters development of nephropathy . Galactose fed AR transgenic mice developed pathological changes in the kidney consistent with nephropathy 98. In other studies, AR activity and TGF-β1 and type IV collagen mRNA levels were significantly increased in glomeruli from transgenic mice (vs wild type mice) exposed to AGE-BSA, in a manner suppressed by the ARI zopolrestat 135.…”

Section: Clinical Applications Of Aris In Humansmentioning

confidence: 78%

“…While deflection of glucose into any of these pathways could exacerbate toxicity, AR is an enzyme that is expressed at extremely low levels in the mouse (see 97 and Figure 2). In an effort to determine if AR deficiency was responsible, in part, for the failure of many mouse models to accelerate atherogenesis with diabetes a transgenic mouse line was created in which human AR (hAR) was expressed via a histocompatibility gene promoter, leading to generalized AR overexpression 98. This transgene led to enzyme levels that were not dissimilar to those in humans.…”

Section: Diabetes-induced Cardiovascular Disease In the Mousementioning

confidence: 99%

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Aldose Reductase and Cardiovascular Diseases, Creating Human-Like Diabetic Complications in an Experimental Model

Ramasamy

Goldberg

2010

Circulation Research

135

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Hyperglycemia and reduced insulin actions affect many biological processes. One theory is that aberrant metabolism of glucose via several pathways including the polyol pathway causes cellular toxicity. Aldose reductase (AR) is a multifunctional enzyme that reduces aldehydes. Under diabetic conditions AR converts glucose into sorbitol, which is then converted to fructose. This article reviews the biology and pathobiology of AR actions. AR expression varies considerably among species. In humans and rats, the higher level of AR expression is associated with toxicity. Flux via AR is increased by ischemia and its inhibition during ischemia reperfusion reduces injury. However, similar pharmacological effects are not observed in mice unless they express a human AR transgene. This is because mice have much lower levels of AR expression, probably insufficient to generate toxic byproducts. Human AR expression in LDL receptor knockout mice exacerbates vascular disease, but only under diabetic conditions. In contrast, a recent report suggests that genetic ablation of AR increased atherosclerosis and increased hydroxynonenal in arteries. It was hypothesized that AR knockout prevented reduction of toxic aldehydes. Like many in vivo effects found in genetically manipulated animals, interpretation requires the reproduction of human-like physiology. For AR, this will require tissue specific expression of AR in sites and at levels that approximate those in humans. (Circ Res. 2010;106:1449-1458.)Key Words: diabetes Ⅲ macrovascular disease Ⅲ atherosclerosis Ⅲ fructose D uring the past decade, studies in genetically modified mice have been used to define processes that contribute to atherosclerosis. Alterations in macrophage and endothelial cell biology by genetic overexpression or deletion can greatly modify vascular lesion extent and also the composition of plaques; these latter effects are viewed as ways to uncover processes leading to plaque instability. Although many processes might alter inflammation and hence lesion extent and complexity, the observation that diabetes/hyperglycemia/ insulin-deficiency alone does not always result in greater Original received November 18, 2009; revision received April 7, 2010; accepted April 8, 2010. From the Departments of Surgery (R.R.) and Medicine (I.J.G.), Columbia University College of Physicians and Surgeons, New York. Correspondence to Dr Ravichandran Ramasamy, Department of Surgery, Columbia University, 630 West 168th St, Black Building 1706a, New York, NY 10032. E-mail rr260@columbia.edu © 2010 American Heart Association, Inc. Many genes are expressed in rodent tissues at levels that are disproportionate to those in humans, and these lead to changes in physiology and response to drugs that are totally different from those of humans. A case in point is the expression of peroxisome proliferator-activated receptor (PPAR) transcription factors. Rodent livers express much higher levels of both PPAR␣ and PPAR␥ than do humans. 2 For this reason, whereas activation of PPAR␣ in rats...

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Section: Clinical Applications Of Aris In Humansmentioning

confidence: 78%

Section: Diabetes-induced Cardiovascular Disease In the Mousementioning

confidence: 99%

Aldose Reductase and Cardiovascular Diseases, Creating Human-Like Diabetic Complications in an Experimental Model

Ramasamy

Goldberg

2010

Circulation Research

135

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“…ARTg mice were obtained from Dr. Mitsuo Itakura (University of Tokushima), and a colony was established at our facility. Briefly, these transgenic mice were developed by injecting full-length human AR (hAR) cDNA with a mouse major histocompatibility antigen class I promoter (43). ARKO mice were generated as described recently (8).…”

Section: Animalsmentioning

confidence: 99%

Aldose reductase modulates cardiac glycogen synthase kinase-3β phosphorylation during ischemia-reperfusion

Abdillahi

Ananthakrishnan

Vedantham

et al. 2012

American Journal of Physiology-Heart and Circulatory Physiology

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Earlier studies have demonstrated that aldose reductase (AR) plays a key role in mediating ischemia-reperfusion (I/R) injury. Our objective was to investigate if AR mediates I/R injury by influencing phosphorylation of glycogen synthase kinase-3β (p-GSK3β). To investigate this issue, we used three separate models to study the effects of stress injury on the heart. Hearts isolated from wild-type (WT), human expressing AR transgenic (ARTg), and AR knockout (ARKO) mice were perfused with/without GSK3β inhibitors (SB-216763 and LiCl) and subjected to I/R. Ad-human AR (Ad-hAR)-expressing HL-1 cardiac cells were exposed to hypoxia (0.5% O(2)) and reoxygenation (20.9% O(2)) conditions. I/R in a murine model of transient occlusion and reperfusion of the left anterior descending coronary artery (LAD) was used to study if p-GSK3β was affected through increased AR flux. Lactate dehydrogenase (LDH) release and left ventricular developed pressure (LVDP) were measured. LVDP was decreased in hearts from ARTg mice compared with WT and ARKO after I/R, whereas LDH release and apoptotic markers were increased (P < 0.05). p-GSK3β was decreased in ARTg hearts compared with WT and ARKO (P < 0.05). In ARKO, p-GSK3β and apoptotic markers were decreased compared with WT (P < 0.05). WT and ARTg hearts perfused with GSK3β inhibitors improved p-GSK3β expression and LVDP and exhibited decreased LDH release, apoptosis, and mitochondrial pore opening (P < 0.05). Ad-hAR-expressing HL-1 cardiac cells, exposed to hypoxia (0.5% O(2)) and reoxygenation (20.9% O(2)), had greater LDH release compared with control HL-1 cells (P < 0.05). p-GSK3β was decreased and correlated with increased apoptotic markers in Ad-hAR HL-1 cells (P < 0.05). Treatment with phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) inhibitor increased injury demonstrated by increased LDH release in ARTg, WT, and ARKO hearts and in Ad-hAR-expressing HL-1 cells. Cells treated with protein kinase C (PKC) α/β inhibitor displayed significant increases in p-Akt and p-GSK3β expression, and resulted in decreased LDH release. In summary, AR mediates changes in p-GSK3β, in part, via PKCα/β and Akt during I/R.

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“…Mice transgenic for hAR were obtained from M. Itakura (University of Tokushima, Tokushima, Japan; Yamaoka et al, 1995), and a colony was established at Columbia University. This line of mice expressing hAR via a histocompatibility antigen class I promoter crossed onto the Ldlr(−/−) background was maintained on a chow diet (Research Diets, Inc., New Brunswick, NJ).…”

Section: Methodsmentioning

confidence: 99%

Regulation of Plasma Fructose and Mortality in Mice by the Aldose Reductase Inhibitor Lidorestat

Noh

Hu²,

Park³

et al. 2008

J Pharmacol Exp Ther

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Aldose reductase (AR), an enzyme widely believed to be involved in the aberrant metabolism of glucose and development of diabetic complications, is expressed at low levels in the mouse. We studied whether expression of human AR (hAR), its inhibition with lidorestat, which is an AR inhibitor (ARI), and the presence of streptozotocin (STZ)-induced diabetes altered plasma fructose, mortality, and/or vascular lesions in low-density lipoprotein (LDL) receptor-deficient [Ldlr(Ϫ/Ϫ)] mice. Mice were made diabetic at 12 weeks of age with low-dose STZ treatment. Four weeks later, the diabetic animals (glucose Ͼ 20 mM) were blindly assigned to a 0.15% cholesterol diet with or without ARI. After 4 and 6 weeks, there were no significant differences in body weights or plasma cholesterol, triglyceride, and glucose levels between the groups. Diabetic Ldlr(Ϫ/Ϫ) mice receiving ARI had plasma fructose levels of 5.2 Ϯ 2.3 g/ml; placebo-treated mice had plasma fructose levels of 12.08 Ϯ 7.4 g/ml, p Ͻ 0.01, despite the induction of fructosemetabolizing enzymes, fructose kinase and adolase B. After 6 weeks, hAR/Ldlr(Ϫ/Ϫ) mice on the placebo-containing diet had greater mortality (31%, n ϭ 9/26 versus 6%, n ϭ 1/21, p Ͻ 0.05). The mortality rate in the ARI-treated group was similar to that in non-hAR-expressing mice. Therefore, diabetic hAR-expressing mice had increased fructose and greater mortality that was corrected by inclusion of lidorestat, an ARI, in the diet. If similar effects are found in humans, such treatment could improve clinical outcome in diabetic patients.Although the relationship between hyperglycemia and a number of vascular disorders is well established, responsible pathways are still unclear. Methods to define these pathways have been hindered by the difficulty of reproducing human diabetic complications in animal models. This has especially been the case for macrovascular disease (Goldberg and Dansky, 2006). In part, this is because of the difficulty of controlling other risk factors in diabetic setting; many atherosclerosisprone diabetic mice become severely hyperlipidemic. Thus, severe hypercholesterolemia in the mouse might obscure the vascular-toxic effects of hyperglycemia (Kanter et al., 2007).Several pathways have been implicated in glucose-induced cellular toxicity (Reusch, 2003). One of these, the polyol pathway, is mediated by the enzyme aldose reductase (AR), an enzyme whose activity is markedly lower in mice than in humans (Hwang et al., 2002;Vikramadithyan et al., 2005). Perhaps, for this reason, by expressing human AR (hAR) in mice, atherosclerosis was increased in the presence of streptozotocin (STZ)-induced diabetes (Vikramadithyan et al., 2005).To determine whether pharmacologic inhibition of AR altered complications in diabetic hAR-expressing LDL receptor knockout [Ldlr(Ϫ/Ϫ)] mice, a blinded study was performed. We first showed that hAR expression and its inhibition alter plasma levels of fructose, a product of the polyol pathway. Lidorestat, a potent AR inhibitor (ARI), reduced mortality r...

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Acute onset of diabetic pathological changes in transgenic mice with human aldose reductase cDNA

Cited by 17 publications

References 13 publications

Aldose Reductase and Cardiovascular Diseases, Creating Human-Like Diabetic Complications in an Experimental Model

Aldose Reductase and Cardiovascular Diseases, Creating Human-Like Diabetic Complications in an Experimental Model

Aldose reductase modulates cardiac glycogen synthase kinase-3β phosphorylation during ischemia-reperfusion

Regulation of Plasma Fructose and Mortality in Mice by the Aldose Reductase Inhibitor Lidorestat

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