Regulation of rat mesangial cell growth by diadenosine phosphates.

Heidenreich, Stefan; Tepel, Martín; Schlüter, Hartmut; Harrach, Balázs; Zidek, Walter

doi:10.1172/jci117992

Cited by 62 publications

(39 citation statements)

References 34 publications

(19 reference statements)

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“…The longer half-life of Ap n A when compared with ATP in extracellular media suggests a role in cellular signalling other than at the synaptic level. In this regard, an effect of Ap n A on the growth of rat renal mesangial cells has been reported [44,45]. In future studies it would be interesting to characterize fully the enzymes that hydrolyse Ap n A from diverse origins, and to investigate their involvement in the control of purinergic signalling.…”

Section: Nucleotidase Cascade : From Ap N a To Adomentioning

confidence: 98%

Diadenosine polyphosphate hydrolase from presynaptic plasma membranes of Torpedo electric organ

Mateo

Rotllán

Martı́

et al. 1997

Biochemical Journal

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The diadenosine polyphosphate hydrolase present in presynaptic plasma membranes from the Torpedo electric organ has been characterized using fluorogenic substrates of the form di-(1,N6-ethenoadenosine) 5´,5‴-P1,Pn-polyphosphate. The enzyme hydrolyses diadenosine polyphosphates (Apn A, where n = 3–5), producing AMP and the corresponding adenosine (n-1) 5´-phosphate, Ap(n-1). The Km values of the enzyme were 0.543± 0.015, 0.478±0.043 and 0.520±0.026 μM, and the Vmax values were 633±4, 592±18 and 576±45 pmol/min per mg of protein, for the etheno derivatives of Ap3A (adenosine 5´,5‴-P1,P3-triphosphate), Ap4A (adenosine 5´,5‴-P1,P4 -tetraphosphate) and Ap5A (adenosine 5´,5‴-P1,P5-pentaphosphate) respectively. Ca2+, Mg2+ and Mn2+ are enzyme activators, with EC50 values of 0.86±0.11, 1.35±0.24 and 0.58±0.10 mM respectively. The fluoride ion is an inhibitor with an IC50 value of 1.38±0.19 mM. The ATP analogues adenosine 5´-tetraphosphate and adenosine 5´-[γ-thio]triphosphate are potent competitive inhibitors and adenosine 5´-[α,β-methylene]diphosphate is a less potent competitive inhibitor, the Ki values being 0.29±0.03, 0.43±0.05 and 7.18±0.8 μM respectively. The P2-receptor antagonist pyridoxal phosphate 6-azophenyl-2´,4´-disulphonic acid behaves as a non-competitive inhibitor with a Ki value of 29.7±3.1 μM, and also exhibits a significant inhibitory effect on Torpedo apyrase activity. The effect of pH on the Km and Vmax values, together with inhibition by diethyl pyrocarbonate, strongly suggests the presence of functional histidine residues in Torpedo diadenosine polyphosphate hydrolase. The enzyme from Torpedo shows similarities with that of neural origin from neurochromaffin cells, and significant differences compared with that from endothelial vascular cells.

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Section: Nucleotidase Cascade : From Ap N a To Adomentioning

confidence: 98%

Diadenosine polyphosphate hydrolase from presynaptic plasma membranes of Torpedo electric organ

Mateo

Rotllán

Martı́

et al. 1997

Biochemical Journal

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“…Moreover, in concentrations Ͼ10 Ϫ8 mol/L diadenosine polyphosphates have a growth-stimulating effect on vascular smooth muscle cells. 10,42,43 Given the EC 50 value for Ap 5 A in the 10…”

Section: Jankowski Et Al Diadenosine Polyphosphates Adrenal Glands mentioning

confidence: 99%

Identification and Quantification of Diadenosine Polyphosphate Concentrations in Human Plasma

Jankowski

Laufer

et al. 2003

ATVB

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Objective-Diadenosine polyphosphates have been demonstrated to be involved in the control of vascular tone as well as the growth of vascular smooth muscle cells and hence, possibly, in atherogenesis. In this study we investigated the question of whether diadenosine polyphosphates are present in human plasma and whether a potential source can be identified that may release diadenosine polyphosphates into the circulation. Methods and Results-Plasma diadenosine polyphosphates (Ap n A with nϭ3 to 6) were purified to homogeneity by affinity-, anion exchange-, and reversed phase-chromatography from deproteinized human plasma. Analysis of the homogeneous fractions with matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) revealed molecular masses ([MϩH] ϩ ) of 757, 837, 917, and 997 d. Comparison of the postsource decay matrix-assisted laser desorption/ionization mass spectrometry mass spectra of these fractions with those of authentic diadenosine polyphosphates revealed that these isolated substances were identical to Ap 3 A, Ap 4 A, Ap 5 A, and Ap 6 A. Enzymatic analysis showed an interconnection of the phosphate groups with the adenosines in the 5Ј-positions of the ribose moieties. The mean total plasma diadenosine polyphosphate concentrations (mol/L; mean Ϯ SEM) in cubital veins of normotensive subjects amounted to 0.89Ϯ0.59 for Ap 3 A, 0.72Ϯ0.72 for Ap 4 A, 0.33Ϯ0.24 for Ap 5 A, and 0.18Ϯ0.18 for Ap 6 A. Cubital venous plasma diadenosine polyphosphate concentrations from normotensives did not differ significantly from those in the hypertensive patients studied. There was no significant difference between arterial and venous diadenosine polyphosphate plasma concentrations in 5 hemodialysis patients, making a significant degradation by capillary endothelial cells unlikely. Free plasma diadenosine polyphosphate concentrations are considerably lower than total plasma concentrations because approximately 95% of the plasma diadenosine polyphosphates were bound to proteins. There were no significant differences in the diadenosine polyphosphate plasma concentrations depending on the method of blood sampling and anticoagulation, suggesting that platelet aggregation does not artificially contribute to plasma diadenosine polyphosphate levels in significant amounts.The Ap n A (with nϭ3 to 6) total plasma concentrations in adrenal veins were significantly higher than the plasma concentrations in both infrarenal and suprarenal vena cava

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“…Furthermore, AP 6 A directly stimulates the proliferation of cultured mesangial cells and augments mesangial cell growth induced by other mitogens released from platelets. 15 These observations demonstrate that AP 6 A may play a role in the pathogenesis and maintenance of hypertension.…”

Section: Discussionmentioning

confidence: 79%

Identification of Diadenosine Hexaphosphate in Human Erythrocytes

Luo¹,

Jankowski²,

Tepel³

et al. 1999

Hypertension

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Abstract-Diadenosine polyphosphates have been identified as important regulators of vascular tone and blood pressure.In reference to the background of the well-known vasoconstriction induced by hemolysate, we questioned whether this action may be due in part to the presence of diadenosine polyphosphates in human erythrocytes. Therefore, erythrocytes were separated from other blood cells and deproteinated. To concentrate and purify nucleotides, the extract was chromatographed by anion exchange, affinity, and reversed-phase columns. In one of the purified fractions, diadenosine hexaphosphate (diadenosine 5Ј, 5Ј-P 1 , P 6 hexaphosphate [AP 6 A]) was identified by matrix-assisted laser desorption/ ionization mass spectrometry, ultraviolet spectroscopy, and enzymatic analysis. Hemolysate of erythrocytes injected into the isolated perfused rat kidney induced a dose-dependent vasoconstriction, which was partially inhibited by P 2 -purinoceptor antagonist. The presence of diadenosine phosphates in granules releasable into the circulation suggests an important role in the control of local perfusion or blood pressure. 1,5,6 Vasoactive action of the diadenosine polyphosphates was demonstrated in numerous vascular models, including most of the physiologically important elements of blood pressure regulation. Diadenosine polyphosphates have different actions on the vasculature, depending on the number of phosphate groups. Diadenosine 5Ј, 5Ј-P 1 , P 2 diphosphate (AP 2 A), diadenosine 5Ј, 5Ј-P 1 , P 3 triphosphate (AP 3 A), and diadenosine 5Ј, 5Ј-P 1 , P 4 tetraphosphate (AP 4 A) are potent vasodilators in the mesenteric and coronary vasculature, 3,5,6 whereas diadenosine 5Ј, 5Ј-P 1 , P 5 pentaphosphate (AP 5 A) and diadenosine 5Ј, 5Ј-P 1 , P 6 hexaphosphate (AP 6 A) appear to have vasoconstrictor properties. 1 The vasoconstrictive effect of hemolysate of dog erythrocytes on dog basilar artery in vitro is caused by ATP. 7 Furthermore, a hypertensive factor that induced a prolonged elevation of blood pressure in normotensive rats has been reported in the erythrocytes of spontaneously hypertensive rats. It appeared that the substance occurred in normotensive as well as hypertensive rats, albeit at a lower concentration in normal animals. 8 Diadenosine tetraphosphate was found to be synthesized within avian erythrocytes. 9 Therefore, in the present study we examined whether diadenosine polyphosphates also exist in human erythrocytes. MethodsBlood from normotensive subjects (men aged 26Ϯ4 years) was collected in tubes containing sodium heparin (1%), and the erythrocyte number was counted. The blood was centrifuged at 2000g at 4°C for 10 minutes, and the plasma together with the buffy coat was discarded. The erythrocytes were washed twice with ice-cold saline. After centrifugation, 5 volumes of ice-cold high-performance liquid chromatography (HPLC)-grade water were added and placed in the refrigerator at 4°C for 20 minutes to hemolyze the erythrocytes. This hemolysate was centrifuged at 6000g for 10 minutes Purification ProceduresT...

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Regulation of rat mesangial cell growth by diadenosine phosphates.

Cited by 62 publications

References 34 publications

Diadenosine polyphosphate hydrolase from presynaptic plasma membranes of Torpedo electric organ

Diadenosine polyphosphate hydrolase from presynaptic plasma membranes of Torpedo electric organ

Identification and Quantification of Diadenosine Polyphosphate Concentrations in Human Plasma

Identification of Diadenosine Hexaphosphate in Human Erythrocytes

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