The role of aldose reductase in sugar cataract formation: aldose reductase plays a key role in lens epithelial cell death (apoptosis)

Murata, Masatoshi; Ohta, Nobuo; Sakurai, Shinichi; Alam, Shahabuddin; Tsai, Jen-Yue; Kador, Peter F.; Sato, Sanai

doi:10.1016/s0009-2797(00)00289-1

Cited by 51 publications

(23 citation statements)

References 12 publications

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“…These results suggest that AR plays an important role in the induction of apoptosis by sorbitol-dependent hyperosmotic stress in cardiomyocytes. This result is also in agreement with data obtained in lens epithelial cells and pancreatic ␤-cells, where apoptosis was dependent on increased AR activation (36,37). Our results also suggest that GSH depletion may be involved in processes leading to induction of apoptosis by hyperosmotic stress in cardiac myocytes.…”

Section: Figsupporting

confidence: 93%

“…The relationship between AR and apoptosis has not been previously examined in the cardiomyocyte. However, in lens epithelial cells and pancreatic ␤-cells, AR activation induced apoptosis, possibly causing an imbalance in redox status (36,37). In cultured retinal pericytes, glucose-induced apoptosis is mediated through the AR pathway, involving increased oxidative stress characterized by reduced GSH contents (38).…”

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confidence: 99%

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Aldose Reductase Induced by Hyperosmotic Stress Mediates Cardiomyocyte Apoptosis

Gálvez

Ulloa

Chiong

et al. 2003

Journal of Biological Chemistry

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Cells adapt to hyperosmotic conditions by several mechanisms, including accumulation of sorbitol via induction of the polyol pathway. Failure to adapt to osmotic stress can result in apoptotic cell death. In the present study, we assessed the role of aldose reductase, the key enzyme of the polyol pathway, in cardiac myocyte apoptosis. Hyperosmotic stress, elicited by exposure of cultured rat cardiac myocytes to the nonpermeant solutes sorbitol and mannitol, caused identical cell shrinkage and adaptive hexose uptake stimulation. In contrast, only sorbitol induced the polyol pathway and triggered stress pathways as well as apoptosis-related signaling events. Sorbitol resulted in activation of the extracellular signal-regulated kinase (ERK), p54 cJun N-terminal kinase (JNK), and protein kinase B. Furthermore, sorbitol treatment resulting in induction and activation of aldose reductase, decreased expression of the antiapoptotic protein Bcl-xL, increased DNA fragmentation, and glutathione depletion. Apoptosis was attenuated by aldose reductase inhibition with zopolrestat and also by glutathione replenishment with N-acetylcysteine. In conclusion, our data show that hypertonic shrinkage of cardiac myocytes alone is not sufficient to induce cardiac myocyte apoptosis. Hyperosmolarity-induced cell death is sensitive to the nature of the osmolyte and requires induction of aldose reductase as well as a decrease in intracellular glutathione levels.

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Section: Figsupporting

confidence: 93%

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confidence: 99%

Aldose Reductase Induced by Hyperosmotic Stress Mediates Cardiomyocyte Apoptosis

Gálvez

Ulloa

Chiong

et al. 2003

Journal of Biological Chemistry

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“…AR, with 71% sequence identity to hARLP, was described as playing a key role in apoptosis. 42,43 Early changes in energy metabolism, including enzymatic alterations associated with excessive storage of glycogen in altered hepatocytes, are typical for experimental hepatocarcinogenesis induced in rats by various chemicals. 44 The excessive glycogen storage reflects changes in various enzymes of carbohydrate metabolism.…”

Section: Discussionmentioning

confidence: 99%

Detection and identification of tumor-associated protein variants in human hepatocellular carcinomas

et al. 2004

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The proteomic approach is a valuable tool to detect and identify proteins that are associated with cancer. In previous investigations on experimentally induced rat hepatomas, we detected aldose reductase-like protein (ARLP) as a highly significant marker protein. Our present study was intended to look for the presence of similar tumor-associated marker proteins on human hepatocellular carcinomas (HCC). We found several novel tumorassociated protein variants that represent members of the aldo-keto reductase (AKR) superfamily. Human aldose reductase-like protein-1 (hARLP-1) was the most prominent tumorassociated AKR member detected in HCC by 2-dimensional electrophoresis (2-DE) and identified by mass spectrometric fingerprinting. The enzyme was found in 4 distinct forms H uman hepatocellular carcinoma (HCC) ranks fifth in worldwide cancer incidence and is an important component of public health. Many HCC risk factors are known, including hepatitis B or C (HBV or HCV) infection, ingestion of aflatoxin-contaminated food, and alcohol. 1,2 The development of HCC is associated with multiple changes at the messenger RNA (mRNA) and/or protein level, some of them serving as tumor markers, e.g., ␣-fetoprotein, 3 or, less specifically, cyclin D1 or the proliferating cell nuclear antigen. 4 Misprogramming of genetic information in cancer is reflected by quantitative and/or qualitative protein alterations. These protein alterations might represent tumor markers that are useful in the diagnosis of human tumors and may also help the understanding of mechanisms of tumor induction and development. Proteome analysis of liver proteins and HCC were predominantly performed using either chemically induced hepatomas in animals (predominantly the rat 5-10 ) or human HCC cell lines, such as HepG2 and Huh7 cells, 11 BEL-7404 cells, 12 or HCC-M cells. 2,13,14 Numerous so-called tumor-associated or cancer-related proteins were identified; these provide valuable information for the establishment of HCC protein databases. 2,[11][12][13][14] Comparative analysis of liver tissue and hepatocellular carcinomas might give additional insights into the induction or repression of tumor-associ-

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“…The enzyme activity has been linked to the causation of diabetic complications including cataractogenesis [39], retinopathy [40], neuropathy [41] and nephropathy [42] . Specific inhibitors of this enzyme that have been used clinically are sorbinil [43], tolrestat [44], epalrestat [45], ranirestat [46, 47], and fidarestat [48].…”

Section: Human Akrs and Diseasementioning

confidence: 99%

The aldo-keto reductases (AKRs): Overview

Penning

2015

Chemico-Biological Interactions

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The aldo-keto reductase (AKR) protein superfamily contains > 190 members that fall into 16 families and are found in all phyla. These enzymes reduce carbonyl substrates such as: sugar aldehydes; keto-steroids, keto-prostaglandins, retinals, quinones, and lipid peroxidation byproducts. Exceptions include the reduction of steroid double bonds catalyzed by AKR1D enzymes (5β-reductases); and the oxidation of proximate carcinogen trans-dihydrodiol polycyclic aromatic hydrocarbons; while the (β-subunits of potassium gated ion channels (AKR6 family) control Kv channel opening. AKRs are usually 37 kDa monomers, have an (α/β)8-barrel motif, display large loops at the back of the barrel which govern substrate specificity, and have a conserved cofactor binding domain. AKRs catalyze an ordered bi bi kinetic mechanism in which NAD(P)H cofactor binds first and leaves last. In enzymes that favor NADPH, the rate of release of NADP+ is governed by a slow isomerization step which places an upper limit on kcat. AKRs retain a conserved catalytic tetrad consisting of Tyr55, Asp50, Lys84, and His117 (AKR1C9 numbering). There is conservation of the catalytic mechanism with short-chain dehydrogenases/reductases (SDRs) even though they show different protein folds. There are 15 human AKRs of these AKR1B1, AKR1C1-1C3, AKR1D1, and AKR1B10 have been implicated in diabetic complications, steroid hormone dependent malignancies, bile acid deficiency and defects in retinoic acid signaling, respectively. Inhibitor programs exist worldwide to target each of these enzymes to treat the aforementioned disorders. Inherited mutations in AKR1C and AKR1D1 enzymes are implicated in defects in the development of male genitalia and bile acid deficiency, respectively, and occur in evolutionary conserved amino acids. The human AKRs have a large number of nsSNPs and splice variants, but in many instances functional genomics is lacking. AKRs and their variants are now poised to be interrogated using modern genomic and informatics approaches to determine their association with human health and disease.

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The role of aldose reductase in sugar cataract formation: aldose reductase plays a key role in lens epithelial cell death (apoptosis)

Cited by 51 publications

References 12 publications

Aldose Reductase Induced by Hyperosmotic Stress Mediates Cardiomyocyte Apoptosis

Aldose Reductase Induced by Hyperosmotic Stress Mediates Cardiomyocyte Apoptosis

Detection and identification of tumor-associated protein variants in human hepatocellular carcinomas

The aldo-keto reductases (AKRs): Overview

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