Enhanced in situ expression of aldose reductase in peripheral nerve and renal glomeruli in diabetic patients

Kasajima, Hiroyuki; Yamagishi, Shin‐Ichiro; Sugai, Satoshi; Yagihashi, Norito; Yagihashi, Soroku

doi:10.1007/s004280100444

Cited by 54 publications

(29 citation statements)

References 43 publications

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“…AR is differentially expressed in mammalian kidney, where AR expression is low under physiological condition in the glomerulus but significantly increased in diabetic human patients (Corder et al, 1979; Kasajima et al, 2001). In diabetic rats, it was found that hyperglycemia-induced increase in glomerular sorbitol levels was attenuated by treatment with an AR inhibitor, sorbinil (Beyer-Mears et al, 1984).…”

Section: Aldose Reductase and Other Complications In Diabetesmentioning

confidence: 99%

Aldose Reductase, Oxidative Stress, and Diabetic Mellitus

Tang¹,

Martin²,

Hwa³

2012

Front. Pharmacol.

360

229

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Diabetes mellitus (DM) is a complex metabolic disorder arising from lack of insulin production or insulin resistance (Diagnosis and classification of diabetes mellitus, 2007). DM is a leading cause of morbidity and mortality in the developed world, particularly from vascular complications such as atherothrombosis in the coronary vessels. Aldose reductase (AR; ALR2; EC 1.1.1.21), a key enzyme in the polyol pathway, catalyzes nicotinamide adenosine dinucleotide phosphate-dependent reduction of glucose to sorbitol, leading to excessive accumulation of intracellular reactive oxygen species (ROS) in various tissues of DM including the heart, vasculature, neurons, eyes, and kidneys. As an example, hyperglycemia through such polyol pathway induced oxidative stress, may have dual heart actions, on coronary blood vessel (atherothrombosis) and myocardium (heart failure) leading to severe morbidity and mortality (reviewed in Heather and Clarke, 2011). In cells cultured under high glucose conditions, many studies have demonstrated similar AR-dependent increases in ROS production, confirming AR as an important factor for the pathogenesis of many diabetic complications. Moreover, recent studies have shown that AR inhibitors may be able to prevent or delay the onset of cardiovascular complications such as ischemia/reperfusion injury, atherosclerosis, and atherothrombosis. In this review, we will focus on describing pivotal roles of AR in the pathogenesis of cardiovascular diseases as well as other diabetic complications, and the potential use of AR inhibitors as an emerging therapeutic strategy in preventing DM complications.

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Section: Aldose Reductase and Other Complications In Diabetesmentioning

confidence: 99%

Aldose Reductase, Oxidative Stress, and Diabetic Mellitus

Tang¹,

Martin²,

Hwa³

2012

Front. Pharmacol.

360

229

View full text Add to dashboard Cite

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“…The notion that NFAT5 is causally linked to these events is supported by the observation that AR is a prototypical NFAT5 target gene [66], and that NFAT5 shows increased DNA binding activity to its consensus sequence in PBMC from patients with diabetic microvascular complications compared with diabetic control subjects under hyperglycemic conditions [62]. Furthermore, enhanced expression of AR is observed in peripheral nerve and renal glomeruli in diabetic patients, and the degree of expression correlates with the disease score [67]. …”

Section: Pathologies Associated With Hyperosmolality and Inflammationmentioning

confidence: 99%

Role of NFAT5 in Inflammatory Disorders Associated with Osmotic Stress

Neuhofer¹

2010

112

119

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Nuclear factor of activated T cells 5 (NFAT5) is the most recently described member of the Rel family of transcription factors, including NF-κB and NFAT1-4, which play central roles in inducible gene expression during the immune response. NFAT5 was initially described to drive osmoprotective gene expression in renal medullary cells, which are routinely faced by high extracellular osmolalities. Recent data however indicate profound biological importance of the mammalian osmotic stress response in view of NFAT5 dependent gene regulation in non-renal tissues. In mononuclear cells and epithelial cells, NFAT5 stimulates the expression of various pro-inflammatory cytokines during elevated ambient tonicity. Accordingly, compared to plasma, the interstitial tonicity of lymphoid organs like spleen and thymus and that of liver is substantially hypertonic under physiological conditions. In addition, anisotonic disorders (hypernatremia, diabetes mellitus, dehydration) entail systemic hyperosmolality, and, in inflammatory disorders, the skin, intestine, and cornea are sites of local hyperosmolality. This article summarizes the current knowledge regarding systemic and local osmotic stress in anisotonic and inflammatory disorders in view of NFAT5 activation and regulation, and NFAT5 dependent cytokine production.

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“…Nevertheless, detailed studies have revealed the presence of AR in mesangial cells (MCs) and in podocytes of the glomeruli [14–16]. Increased expression of the enzyme has been demonstrated in the glomeruli of diabetic patients [17], while both mRNA and activity of AR were elevated in rat mesangial cells cultured in high glucose [18]. …”

Section: Introductionmentioning

confidence: 99%

Osmolarity and Glucose Differentially Regulate Aldose Reductase Activity in Cultured Mouse Podocytes

Lewko

Latawiec

Maryn

et al. 2011

Experimental Diabetes Research

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Podocyte injury is associated with progression of many renal diseases, including diabetic nephropathy. In this study we examined whether aldose reductase (AR), the enzyme implicated in diabetic complications in different tissues, is modulated by high glucose and osmolarity in podocyte cells. AR mRNA, protein expression, and activity were measured in mouse podocytes cultured in both normal and high glucose and osmolarity for 6 hours to 5 days. Hyperosmolarity acutely stimulated AR expression and activity, with subsequent increase of AR expression but decrease of activity. High glucose also elevated AR protein level; however, this was not accompanied by respective enzyme activation. Furthermore, high glucose appeared to counteract the osmolarity-dependent activation of AR. In conclusion, in podocytes AR is modulated by high glucose and increased osmolarity in a different manner. Posttranslational events may affect AR activity independent of enzyme protein amount. Activation of AR in podocytes may be implicated in diabetic podocytopathy.

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Enhanced in situ expression of aldose reductase in peripheral nerve and renal glomeruli in diabetic patients

Cited by 54 publications

References 43 publications

Aldose Reductase, Oxidative Stress, and Diabetic Mellitus

Aldose Reductase, Oxidative Stress, and Diabetic Mellitus

Role of NFAT5 in Inflammatory Disorders Associated with Osmotic Stress

Osmolarity and Glucose Differentially Regulate Aldose Reductase Activity in Cultured Mouse Podocytes

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