Decreased Expression of Adenosine Kinase in Streptozotocin-Induced Diabetes Mellitus Rats

Pawełczyk, Tadeusz; Sakowicz, Monika; Szczepańska-Konkel, M; Angielski, Stefan

doi:10.1006/abbi.1999.1548

Cited by 50 publications

(46 citation statements)

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“…In this regard, enhanced renal adenosine excretion occurs during acute renal injury, [39] and kidneys from diabetic rats are not only more sensitive to renal vascular and growth inhibitory effects of adenosine, but also have a greater capacity to produce and maintain higher extracellular concentrations of adenosine. [40][41][42][43] Importantly, caffeine reduced renal adenosine excretion, suggesting reduced renal production and extracellular levels of adenosine. In obese animals, caffeine also increased renal excretion of cAMP, which is consistent with reported inhibition of phosphodiesterase by caffeine.…”

Section: Discussionmentioning

confidence: 96%

Early Renal Injury Induced by Caffeine Consumption in Obese, Diabetic ZSF₁Rats

et al. 2007

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Our previous studies indicate that prolonged caffeine consumption exacerbates renal failure in nephropathy associated with the metabolic syndrome. Reduced activity of the antioxidant defense system and beneficial effects of antioxidant therapy have been reported in diabetic rats and humans. The purpose of this study was to examine the early renal effects of caffeine consumption and the effects of concomitant antioxidant therapy in young obese, diabetic ZSF1 rats. Eleven-week-old male ZSF1 rats were randomized to drink tap water, caffeine (0.1%), tempol (1 mmol/ L), or a solution containing caffeine and tempol for nine weeks. Caffeine significantly reduced body weight and glycosuria (weeks 2-9), improved glucose tolerance (week 9), had no effect on elevated plasma triglycerides, plasma cholesterol (week 9) and blood pressure (week 9), and significantly increased plasma cholesterol level (weeks 5 and 9). Yet, as early as after two weeks, caffeine greatly augmented proteinuria and increased renal vascular resistance (RVR) and heart rate (HR: week 9). Tempol had no effects on metabolic status and development of proteinuria, did not alter caffeine-induced metabolic changes and early proteinuria, and attenuated caffeine-induced increase in HR and RVR. Immunohistochemical analysis revealed significant glomerular and interstitial inflammation, proliferation, and fibrosis in control animals. Caffeine augmented the influx of glomerular and interstitial macrophages (ED1+ cells) influx, glomerular and tubular proliferative response, and glomerular collagen IV content. Tempol abolished the exacerbation of renal inflammation, proliferation, and fibrosis induced by caffeine. In conclusion, in nephropathy associated with the metabolic syndrome, caffeine-most likely through the interaction with adenosine receptors and interference with anti-inflammatory and/or glomerular hemodynamic effects of adenosine-augments proteinuria and stimulates some of the key proliferative mechanisms involved in glomerular remodeling and sclerosis. Tempol does not prevent early renal injury (i.e., proteinuria) induced by caffeine, yet abolishes late renal inflammatory, proliferative, and fibrotic change induced by chronic caffeine consumption in obese ZSF1 rats.

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Section: Discussionmentioning

confidence: 96%

Early Renal Injury Induced by Caffeine Consumption in Obese, Diabetic ZSF₁Rats

et al. 2007

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“…Previously, we have demonstrated that the activity of adenosine kinase, which is considered a very sensitive control point for adenosine levels in the cell, is significantly decreased in diabetic kidney. 11 This suggests that the turnover of the AMP-adenosine metabolic cycle might be impaired in diabetic kidney leading to local increases in adenosine concentration. This assumption is supported by experiments indicating that in the kidney of diabetic rats adenosine levels were not altered in the artery but increased significantly in plasma of the renal vein.…”

Section: Discussionmentioning

confidence: 99%

“…Changes in 5Ј-NT and ADA activity were observed only in the membrane fraction of diabetic kidney but not in cytosol. 11 …”

Section: Ada and 5ј-nucleotidase (5ј-nt) Activities In Kidney Membranesmentioning

confidence: 99%

“…10 Moreover, the expression level of adenosine kinase in the diabetic kidney was greatly reduced, suggesting that the turnover of the adenosine-AMP metabolic cycle might be impaired under diabetic conditions. 11 The present studies were designed to examine the expression level of adenosine receptors (ARs) in diabetic kidney. The results show zone-dependent alterations in expression level of ARs in diabetic kidney.…”

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confidence: 99%

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Region-Specific Alterations of Adenosine Receptors Expression Level in Kidney of Diabetic Rat

Pawełczyk

Grdeń

Rzepko

et al. 2005

The American Journal of Pathology

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Pathological alterations of renal function in insulindependent diabetes have been attributed to numerous factors, including adenosine. This study examined the expression levels of adenosine receptors (ARs) in the kidney of the streptozotocin-induced diabetic rat. In the diabetic kidney A1-AR mRNA levels increased 1.7-and 2.8-fold in cortex and medulla, respectively. This was accompanied by increased A1-AR protein levels in membranes of kidney cortex (1.5-fold) and medulla (threefold). A1-AR immunoreactivity increased strongly along medullar tubules especially in the collecting duct. The levels of A2a-AR mRNA increased twofold in diabetic kidney cortex but remained unchanged in medulla; however, A2a-AR protein levels increased more than threefold in cortex. Immunohistochemistry showed increased A2a-AR immunoreactivity in luminal membranes of cortical collecting ducts and in epithelial cells of preglomerular vessels. There were no significant changes in A2b-AR expression in diabetic kidney except in medullar membranes, where the receptor protein content decreased by 60%. A3-AR mRNA levels in diabetic kidney remained unchanged, but membrane-associated A3-AR protein levels increased by 70% in diabetic kidney cortex and decreased by 80% in medulla. These changes in ARs genes expression, receptor protein content, and cellular and tissue distribution, correspond to abnormalities characteristic of the diabetic kidney, suggesting involvement in pathogenesis of diabetic nephropathy. Kidney disease is one of the leading hallmarks of human diabetes. It is characterized by persistent proteinuria, hypertension, and progressive loss of renal function. 1These changes are preceded by glomerular hyperfiltration, which is an early symptom in the development of diabetic nephropathy.2,3 Pathological changes of renal function in insulin-dependent diabetes have been attributed to numerous factors, including impaired action of angiotensin II, NO, prostaglandins, and adenosine. 4 -7 Adenosine in the kidney plays a broad regulatory role including modulation of renal blood flow, glomerular filtration rate, hormone and neurotransmitter release, transport function, and urine flow.8 Therefore, any changes in its action may significantly affect function of this organ.Adenosine is formed both in the extra-and intracellular space and exerts its physiological effect by coupling to cell-surface receptors, namely A1, A2a, A2b, and A3. The affinity for adenosine varies between receptors; thus its activation depends on adenosine concentration. The level of adenosine depends on its metabolism and transport across plasma membranes. Our previous studies showed that, except for ENT2, the expression level of nucleoside transporters in kidney of diabetic rats was not altered. 10 Moreover, the expression level of adenosine kinase in the diabetic kidney was greatly reduced, suggesting that the turnover of the adenosine-AMP metabolic cycle might be impaired under diabetic conditions. 11

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“…These late-phase changes are believed to result from early responses of myocardium to suddenly increased glucose levels (1,6 -8). Early responses of myocardial cells to hyperglycemia include metabolic abnormalities, subcellular defects, abnormal expression of genes (7)(8)(9), and, consequently, cardiac cell death (8,10,11).…”

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confidence: 99%

Hyperglycemia-Induced Apoptosis in Mouse Myocardium

et al. 2002

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Diabetic cardiomyopathy is related directly to hyperglycemia. Cell death such as apoptosis plays a critical role in cardiac pathogenesis. Whether hyperglycemia induces myocardial apoptosis, leading to diabetic cardiomyopathy, remains unclear. We tested the hypothesis that apoptotic cell death occurs in the diabetic myocardium through mitochondrial cytochrome c-mediated caspase-3 activation pathway. Diabetic mice produced by streptozotocin and H9c2 cardiac myoblast cells exposed to high levels of glucose were used. In the hearts of diabetic mice, apoptotic cell death occurred as detected by terminal deoxynucleotidyl transferasemediated dUTP nick-end labeling (TUNEL) assay. Correspondingly, caspase-3 activation as determined by enzymatic assay and mitochondrial cytochrome c release detected by Western blotting analysis were observed. Supplementation of insulin inhibited diabetesinduced myocardial apoptosis as well as suppressed hyperglycemia. To explore whether apoptosis in diabetic hearts is related directly to hyperglycemia, we exposed cardiac myoblast H9c2 cells to high levels of glucose (22 and 33 mmol/l) in cultures. Apoptotic cell death was detected by TUNEL assay and DAPI nuclear staining. Caspase-3 activation with a concomitant mitochondrial cytochrome c release was also observed. Apoptosis or activation of caspase-3 was not observed in the cultures exposed to the same concentrations of mannitol. Inhibition of caspase-3 with a specific inhibitor, Ac-DEVD-cmk, suppressed apoptosis induced by high levels of glucose. In addition, reactive oxygen species (ROS) generation was detected in the cells exposed to high levels of glucose. These results suggest that hyperglycemia directly induces apoptotic cell death in the myocardium in vivo. Hyperglycemiainduced myocardial apoptosis is mediated, at least in part, by activation of the cytochrome c-activated caspase-3 pathway, which may be triggered by ROS derived from high levels of glucose.

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Decreased Expression of Adenosine Kinase in Streptozotocin-Induced Diabetes Mellitus Rats

Cited by 50 publications

References 30 publications

Early Renal Injury Induced by Caffeine Consumption in Obese, Diabetic ZSF₁Rats

Early Renal Injury Induced by Caffeine Consumption in Obese, Diabetic ZSF₁Rats

Region-Specific Alterations of Adenosine Receptors Expression Level in Kidney of Diabetic Rat

Hyperglycemia-Induced Apoptosis in Mouse Myocardium

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Decreased Expression of Adenosine Kinase in Streptozotocin-Induced Diabetes Mellitus Rats

Cited by 50 publications

References 30 publications

Early Renal Injury Induced by Caffeine Consumption in Obese, Diabetic ZSF1Rats

Early Renal Injury Induced by Caffeine Consumption in Obese, Diabetic ZSF1Rats

Region-Specific Alterations of Adenosine Receptors Expression Level in Kidney of Diabetic Rat

Hyperglycemia-Induced Apoptosis in Mouse Myocardium

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Early Renal Injury Induced by Caffeine Consumption in Obese, Diabetic ZSF₁Rats

Early Renal Injury Induced by Caffeine Consumption in Obese, Diabetic ZSF₁Rats