Tissue levels of S-adenosylhomocysteine in the rat kidney: effects of ischemia and homocysteine

Kloor, Doris; Delabar, Ursula; Mühlbauer, Bernd; Luippold, Gerd; Oßwald, Hartmut

doi:10.1016/s0006-2952(01)00892-9

Cited by 35 publications

(52 citation statements)

References 32 publications

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“…The kidneys were pulverized under liquid nitrogen, and the tissue protein was precipitated with 0.6N ice-cold perchloric acid. Tissue adenosine levels were determined via HPLC-UV as previously described (81,82). To validate the HPLC-UV results, we ran the same samples with HPLC-MS/MS (Supplemental Figure 1, A and B).…”

Section: Methodsmentioning

confidence: 99%

Equilibrative nucleoside transporter 1 (ENT1) regulates postischemic blood flow during acute kidney injury in mice

Grenz¹,

Bauerle²,

Dalton³

et al. 2012

J. Clin. Invest.

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114

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A complex biologic network regulates kidney perfusion under physiologic conditions. This system is profoundly perturbed following renal ischemia, a leading cause of acute kidney injury (AKI) -a life-threatening condition that frequently complicates the care of hospitalized patients. Therapeutic approaches to prevent and treat AKI are extremely limited. Better understanding of the molecular pathways promoting postischemic reflow could provide new candidate targets for AKI therapeutics. Due to its role in adapting tissues to hypoxia, we hypothesized that extracellular adenosine has a regulatory function in the postischemic control of renal perfusion. Consistent with the notion that equilibrative nucleoside transporters (ENTs) terminate adenosine signaling, we observed that pharmacologic ENT inhibition in mice elevated renal adenosine levels and dampened AKI. Deletion of the ENTs resulted in selective protection in Ent1 -/-mice. Comprehensive examination of adenosine receptor-knockout mice exposed to AKI demonstrated that renal protection by ENT inhibitors involves the A2B adenosine receptor. Indeed, crosstalk between renal Ent1 and Adora2b expressed on vascular endothelia effectively prevented a postischemic no-reflow phenomenon. These studies identify ENT1 and adenosine receptors as key to the process of reestablishing renal perfusion following ischemic AKI. If translatable from mice to humans, these data have important therapeutic implications. IntroductionAcute kidney injury (AKI) is clinically defined by an abrupt reduction in kidney function (e.g., a decrease in glomerular filtration rate [GFR]), occurring over a period of minutes to days. AKI is frequently caused by an obstruction of renal blood flow (renal ischemia) and represents an important cause of morbidity and mortality of patients (1-3). Indeed, a recent study revealed that only a mild increase (0.3 mg/dl) in the serum creatinine level is associated with a 70% greater risk of death than in patients without this increase (2, 3). Particularly for surgical patients, AKI represents a significant threat. For example, surgical procedures requiring cross-clamping of the aorta and renal vessels are associated with a rate of AKI of up to 30% (4). Similarly, AKI after cardiac surgery occurs in up to 10% of patients under normal circumstances and is associated with dramatic increases in mortality (5). In addition, patients with sepsis frequently go on to develop AKI, and the combination of moder-

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Section: Methodsmentioning

confidence: 99%

Equilibrative nucleoside transporter 1 (ENT1) regulates postischemic blood flow during acute kidney injury in mice

Grenz¹,

Bauerle²,

Dalton³

et al. 2012

J. Clin. Invest.

Self Cite

114

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“…This is in strong contrast to the study by Chen et al, which demonstrated an Ϸ50% reduction in endogenous baseline adenosine concentration induced by mild elevation of plasma homocysteine from 6.7Ϯ0.4 to 14.7Ϯ0.5 mol/L. 2 This discrepancy could be caused by the differences between man and rat concerning protein-binding of homocysteine, 6 AdoHcy hydrolase activity, 3 and characteristics of the equilibrative nucleoside transporter. 32 Also, the experimental methionine-induced hyperhomocysteinemia in the rat model differs from the hyperhomocysteinemia in our patient group, possibly affecting tissue and cellular distribution of homocysteine.…”

Section: Discussionmentioning

confidence: 77%

“…5 Previous animal studies suggest that the effect of intracellular AdoHcy formation on the transmembranous adenosine gradient and thus diffusion of extracellular adenosine into the cells is most pronounced in these very situations of high concentrations of adenosine, thus limiting adenosine receptor stimulation when most needed. 6,7 Therefore, we speculate that in hyperhomocysteinemia, decreased extracellular adenosine concentrations contribute to the development of the associated cardiovascular problems.…”

mentioning

confidence: 99%

Enhanced Cellular Adenosine Uptake Limits Adenosine Receptor Stimulation in Patients With Hyperhomocysteinemia

Riksen

Rongen

Boers

et al. 2005

ATVB

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Objective-Endogenous adenosine has several cardioprotective effects. We postulate that in patients with hyperhomocysteinemia increased intracellular formation of S-adenosylhomocysteine decreases free intracellular adenosine. Subsequently, facilitated diffusion of extracellular adenosine into cells through dipyridamole-sensitive transporters is enhanced, limiting adenosine receptor stimulation. We tested this hypothesis in patients with classical homocystinuria (nϭ9, plasma homocysteine 93.1Ϯ24.7 mol/L) and matched controls (nϭ8, homocysteine 9.1Ϯ1.0). Methods and Results-Infusion of adenosine (0.5, 1.5, 5.0, and 15.0 g/min/dL forearm) into the brachial artery increased forearm blood flow, as measured with venous occlusion plethysmography, to 2.9Ϯ0.4, 4.3Ϯ0.5, 5.6Ϯ1.1, and 9.6Ϯ2.1 in the patients and to 2.8Ϯ0.6, 4.4Ϯ1.0, 9.0Ϯ1.7, and 17.0Ϯ3.1 mL/min/dL in controls (PϽ0.05). However, adenosine-induced vasodilation in the presence of dipyridamole (100 g/min/dL) was similar in both groups (Pϭ0.9). Additionally, in isolated erythrocytes, adenosine uptake was accelerated by incubation with homocysteine (half-time 6.4Ϯ0.3 versus 8.1Ϯ0.5 minutes, PϽ0.001) associated with increased intracellular formation of S-adenosylhomocysteine (PϽ0.0001). Conclusions-In hyperhomocysteinemia, adenosine-induced vasodilation is impaired but is restored by dipyridamole.Accelerated cellular adenosine uptake probably accounts for these observations. These impaired actions of adenosine could well contribute to the cardiovascular complications of hyperhomocysteinemia. Key Words: adenosine Ⅲ hyperhomocysteinemia Ⅲ dipyridamole Ⅲ forearm Ⅲ nucleoside transport H yperhomocysteinemia is an independent risk factor for atherosclerosis and thromboembolism. It is poorly understood which mechanism is responsible for these cardiovascular complications.Recently, we and others have drawn attention to a new hypothesis, focusing on the influence of homocysteine on the metabolism of the endogenous nucleoside adenosine. 1,2 According to this hypothesis, a homocysteine-induced fall in extracellular adenosine contributes to the cardiovascular sequelae of hyperhomocysteinemia. Fundamental to this is the reversibility of the reaction in which S-adenosylhomocysteine (AdoHcy) is hydrolyzed to form homocysteine and adenosine. 3 Although the equilibrium constant of this reaction favors AdoHcy synthesis, under physiological conditions AdoHcy is hydrolyzed to homocysteine and adenosine, because both reaction products are rapidly metabolized. In hyperhomocysteinemia, the reaction shifts toward AdoHcy synthesis at the expense of free intracellular adenosine. Subsequently, facilitated diffusion of extracellular adenosine into the cells through the dipyridamole-sensitive equilibrative nucleoside transporter is enhanced, limiting stimulation of membrane-bound adenosine receptors (Figure 1).By stimulation of these receptors, extracellular adenosine induces several effects, which could protect against the development of atherosclerosis and thrombosis and against ischemia-re...

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“…Because adenosine inhibits in vitro SAH hydrolase activity in nanomolar concentrations, this action would increase cytosolic SAH levels and thus diminish the methylation potential [the ratio of S-adenosylmethionine (SAM) to SAH], which regulates transmethylation reactions in the cell. Moreover, it was shown that renal tissue content of SAH increases severalfold after ischemia (161). In this respect, it is of interest to note that in addition to being expressed in the cytosol of nearly all kidney cells, a prominent staining of SAH hydrolase can be seen in the nuclei of podocytes (164) and that SAH hydrolase accumulates in nuclei of transcriptional activated cells (275).…”

Section: S-adenosylhomocysteine Hydrolase Binds Adenosinementioning

confidence: 99%

Adenosine and Kidney Function

Vallon

Mühlbauer²,

Oßwald³

2006

Physiological Reviews

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379

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In this review we outline the unique effects of the autacoid adenosine in the kidney. Adenosine is present in the cytosol of renal cells and in the extracellular space of normoxic kidneys. Extracellular adenosine can derive from cellular adenosine release or extracellular breakdown of ATP, AMP, or cAMP. It is generated at enhanced rates when tubular NaCl reabsorption and thus transport work increase or when hypoxia is induced. Extracellular adenosine acts on adenosine receptor subtypes in the cell membranes to affect vascular and tubular functions. Adenosine lowers glomerular filtration rate (GFR) by constricting afferent arterioles, especially in superficial nephrons, and acts as a mediator of the tubuloglomerular feedback, i.e., a mechanism that coordinates GFR and tubular transport. In contrast, it leads to vasodilation in deep cortex and medulla. Moreover, adenosine tonically inhibits the renal release of renin and stimulates NaCl transport in the cortical proximal tubule but inhibits it in medullary segments including the medullary thick ascending limb. These differential effects of adenosine are subsequently analyzed in a more integrative way in the context of intrarenal metabolic regulation of kidney function, and potential pathophysiological consequences are outlined.

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Tissue levels of S-adenosylhomocysteine in the rat kidney: effects of ischemia and homocysteine

Cited by 35 publications

References 32 publications

Equilibrative nucleoside transporter 1 (ENT1) regulates postischemic blood flow during acute kidney injury in mice

Equilibrative nucleoside transporter 1 (ENT1) regulates postischemic blood flow during acute kidney injury in mice

Enhanced Cellular Adenosine Uptake Limits Adenosine Receptor Stimulation in Patients With Hyperhomocysteinemia

Adenosine and Kidney Function

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