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Copyrig Interaction of intrarenal adenosine and angiotensin II in kidney vascular resistance Marth la Introduction The regulation of renal blood flow, glomerular capillary pressure and glomerular hemodynamics is under the control of the tubuloglomerular feedback mechanism, an intrinsic mechanism of the kidney [1,2]. This mech- anism adjusts the tone of the afferent and efferent arterioles according to the sodium load sensed by the macula densa cells. The resistance of the arterioles is affected by several vasoactive compounds that can function as mediators or modulators of the vascular tone, such as angiotensin II (AngII) and adenosine (ADO) [3]. This review will focus in the intrinsic mechanism involved in the ADO-AngII, interaction, a recognized phenomenon described in 1979 [4], that continu cited in on the Regulation of vascular tone The essential event that induces vasoconstriction involves cytosolic Ca2þ; however there are many mech- anisms that increase cytosolic calcium, which in turn activate calmodulin andmyosin light chain kinase. These mechanisms can be separated into those involving increases in cellular entry of Ca2þ, via membrane chan- nels, and those primarily involving release of Ca2þ from intracellular stores. Of great importance is the role of voltage-dependent Ca2þ channels in regulating vascular smooth muscle tone primarily in preglomerular arterioles, and intracellular release in efferent arterioles, as calcium is the main effector of the autoregulatory response [5,6]. aDepartme Cardiologı´a Fedral and Medicina U Correspond Departmen Cardiologı´a Mexico Cit Tel: +5255 e-mail: mar Current O Hypertens II ( tio acti m b tha in vas log mp pr her The ADO-metabolizing enzymes have become important regulators of the effects of ADO on the tone of the afferent and efferent arterioles. As AngII is able to increase de-novo renal ADO content through decrease of ADO-metabolizing enzymes, accumulation of ADO induces downregulation of ADO A2 receptor population without modifying ADO A1 receptor, thereby enhancing the constrictive effects of AngII in the renal vasculature. Keywords adenosine, adenosine deaminase, adenosine receptors, angiotensin II, angiotensin II AT1 receptors, ecto-50-nucleotidase Curr Opin Nephrol Hypertens 18:63–67 � 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins 1062-4821 1062-482 es under investigation. Some old papers are order of provide an appropriate background field. A predominant effect of voltage Ca2þ channels has been observed on preglomerular arterioles, thus calcium channel blockers vasodilate the afferent arterioles, having 1 � 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins DOI:10.1097/MNH.0b013e32831cf5d3 a Francoa, Oscar Pe´rez-Mende´za and F nt of Nephrology, Instituto Nacional de ‘Ignacio Cha´vez’, Me´xico City, Distrito bDepartment of Pharmacology, Facultad de ASLP, San Luis Potosı´, Mexico ence to Martha Franco, MD, PhD, t of Nephrology, Instituto Nacional de ‘Ignacio Cha´vez’, Juan Badiano No.1, y, 14080 D.F., Mexico 573 6902; fax: +5255 573 7716; thafranco@lycos.com pinion in Nephrology and ion 2009, 18:63–67 Purpose of the review The adenosine–angiotensin regulation of glomerular filtra feedback. Although the inter mechanisms of the synergis understood. Recent findings Current evidence suggests 50-nucleotidase or ADO deam play an important role in the afferent arterioles when tubu concentration induced by te ADO receptors, leading to a ADO receptors balance furt and AngII. Summary ht © Lippincott Williams & Wilkins. Unauthorized vio Martı´nezb ADO-AngII) interaction plays an important role in the n rate, vascular resistance and tubuloglomerular on was described more than 30 years ago, the intrinsic etween both autacoids remains incompletely t ADO-metabolizing enzymes such as ecto- ase, as well as enzymes that degrade ATP to adenosine, oconstrictor signals sent from the macula densa to the lomerular feedback is activated; increased ADO oral infusion of AngII results in downregulation of A2 edominant effect of A1 receptors; the alteration in the contributes to the synergic interaction between ADO reproduction of this article is prohibited. Copyrigh minimal effect on efferent arterioles. The observations mentioned earlier suggest that Ca2þ influx through vol- tage-gat of affere are mor intracel investig channel T-type ent and efferent which a Regula Adenos A1 ADO tors (A2 the blo aration, respond adenosi trations to contr tors [10 dilation significa tor ant A2a AD vations A1-indu postglom In this mouse 10�11 to fused a the dia tration r an initia of A2 re agonist) ADO r more, t constric vasosod ADO re control effect o Recent that AD [13�]. T Western demons recepto of ADO receptors [14] has been reported in the efferent arteriole. he it on os n o on l. ase an re tio d 3-m A she -in in x o co c cti atio ati ula o to s in rta cs, ]. 12/ to pa pa tol th gh um enh th ts aci ts i du th oic . F lin er ati e af 64 Circulation and hemodynamics ceptor, as well A2a and A2b ADO receptors in the of afferent arteriolar tone shows a predominant f A1 receptor [11]. studies in isolated efferent arterioles point out O only induces vasodilation in these vessels he expression of ADO receptors shown by blotting, Northern blotting and RT-PCR have trated abundant expression of A1 and A2b rs in the afferent arteriole but no expression tidic resul A2 in olites traen [17�] signa block indic in th ed channels is fairly important in the regulation nt arteriolar tone. In contrast, efferent arterioles e dependent on other mechanisms that induce lular Ca2þ mobilization [5]. In this regard, the ation of Ca2þ subtypes has revealed that L-type s are only distributed in the afferent arteriole, and and N-type channels are distributed in the affer- efferent arterioles [5,7�]. Thus, afferent and arterioles have distinct activation mechanisms, llow different responses to several stimuli. tion of vascular tone by adenosine ine receptors mediate renal vasoconstriction via receptors and vasodilation via A2 ADO recep- a and A2b) [8,9]. It has been demonstrated in od-perfused rat juxtamedullary nephron prep- that both afferent and efferent arterioles to adenosine with vasoconstriction at a low ne concentration; however, at high concen- the arteriolar diameters return to values similar ol, indicating the activation of A2 ADO recep- ,11]. A1 ADO receptor blockade induces vaso- in afferent and efferent arterioles, which is ntly attenuated by the addition of an A2a recep- agonist, suggesting the presence of A1 and O receptors in both arterioles [10]; these obser- suggest that A2a receptors may buffer the ced vasoconstriction in the preglomerular and erular arterioles [12�]. regard, recent studies in isolated and perfused afferent arterioles have demonstrated that ADO 10�9mol/l reduces the diameter of microper- fferent arterioles attached to the glomeruli, and meter returns to control values at the concen- ange between 10�8 to 10�4mol/l [11], suggesting l activation of A1 receptors followed by activation ceptors; in addition, in this study CPA (A1 ADO induces vasoconstriction and CGS21680 (A2a eceptor agonist) induces vasodilation. Further- he use of a specific A1 antagonist prevents the tion response and an A2a antagonist inhibits the ilatory effect, thus the physiological role of the A1 On t ioles vasoc of ph bitio the c et a incre lated was deple vente an IP as an aboli ADO that influ nels patch the a activ medi Reg Most recep ance impo nami [16�� Gaq recep pholi pholi inosi C, wi throuCalci and smoo resul t © Lippincott Williams & Wilkins. Unauthorized nt role in the control of glomerular hemody- glomerular filtration rate and TG feedback The AT1 receptor is coupled to Gaq/11, 13 and Gbg complexes. The stimulation of this r results in activation of phospholipase C, phos- se A2 and phospholipase D; activation of phos- se C induces formation of diacylglycerol and trisphosphate, which activates protein kinase a consequent increase of free intracellular calcium calcium efflux from the sarcoplasmic reticulum. binds to calmodulin, activatesmyosin light chain ances actin and myosin interaction, leading to muscle contraction. Phospholipase D activation in hydrolysis of phosphatidilcholine to phospha- d, diacylglycerol, protein kinase C activation that nmuscle contraction. Activation of phospholipase ces liberation of arachidonic acid and its metab- romboxan A2, leukotrienes and hydroxyeicosate- acid, all of them with vasoconstrictor properties or a complete review of other AngII effects on g see reference [17�]. Furthermore, Ca2þ channel s prevent the constriction induced by AngII, ng that L-type Ca2þ channels are only present ferent vessels and T-type Ca2þ channels regulate contrary, in isolated and perfused afferent arter- has been demonstrated that adenosine-induced striction is mediated by Gi/Go-coupled activation pholipase C. In this context, Gi-dependent inhi- f adenylate cyclase seems to play a minor role in strictive response [15]. In further studies, Hansen [16��] demonstrated that ADO significantly s the intracellular calcium concentration in iso- d perfused mouse afferent arterioles; the calcium leased from the sarcoplasmic reticulum, as n of intracellular Ca2þ stores completely pre- the constrictor response to ADO. In addition, ediated pathway mediated the calcium release, DO dose–response relationship is completely d by a specific IP3 antagonist. Inhibition of the duced vasoconstriction by nifedipine indicates addition to the mechanisms mentioned earlier, f calcium through voltage-dependent Ca2þ chan- ntributes to maintain cytosolic calcium levels; lamp experiments in this study demonstrated vation of a depolarizing chloride current. The n of protein kinase C was not involved in the on of contraction induced by ADO [16��]. tion of vascular tone by angiotensin II f the actions of AngII are mediated by type 1 rs (AT1), and regulate afferent and efferent resist- a dose dependent manner; thus AngII plays an reproduction of this article is prohibited. Copyrig afferent and efferent resistances. The role of T-type Ca2þ channels on efferent arterioles may contribute to the vasocon Synerg angiot Conside betwee studies the vas extent thus, A effects conditio Of parti in whic to AngI effects carried perform follow t strictor the mo recepto zation microva isolated applied sitizatio observe arteriola the con have co the AD desensi ent arte 10�4mo was sig without 30min when N in the A with AD AngII. changes ioles, b transpo fact, th myosin enhance suggest tation in and ML that the not med �� In addition, important evidence has been obtained from gene-manipulated mice; in A1 ADO receptor deficient , th ns res An sen gs ef an of art ga atio pin ng rth ase re pha ed e afferent arterioles; this enzyme has the ability to osp rat osp ac . T ��, ns iole ot be co . ula m iot ter the ion ell te ] t te s c ng nt in mi r rat s er Angiotensin II–adenosine interaction in the kidney Franco et al. 65 iated by ADO receptors [20 ]. block striction elicited by AngII [18]. ic interaction between adenosine and ensin II rable evidence suggests a synergic interaction n AngII and ADO in the renal vessels. Elegant have demonstrated in in-vivo experiments that oconstriction caused by ADO depends on the of activation of the renin–angiotensin system; ngII depleted states decrease the constrictor of ADO; in contrast, under AngII high activity ns, the constrictor effects of ADO are larger [3]. cular importance are the cross-blockade studies, h specific ADO blockers decrease the response I as well as AngII blockers interference with the of ADO or ADO A1 agonists [3]. Most studies out in isolated afferent arterioles, as well as those ed in the isolated juxtaglomerular preparation, he same pattern. In afferent arterioles, vasocon- effects are observed and the effect is higher in st distal part of the vessel [1]. In addition, a r-independent effect of ADO on the desensiti- of AngII–induced contractions in the renal sculature has been proposed. Lai et al. [19], in and perfused afferent arterioles, successively AngII for 2min on the bath side; a clear desen- n of the AngII-induced contraction was d. Addition of adenosine did not change the r diameter; however, ADO treatment restored tractile response to AngII. Patzak et al. [20��] ntinued studying the mechanisms involved in O restoration of AngII vasoconstriction after tization; in this work isolated and perfused affer- rioles were treated with ADO from 10�11 to l/l, followed by AngII; the effect of this peptide nificantly larger after ADO pretreatment than pretreatment, and the effect remained after of ADO pretreatment; this was not observed 6-cyclopentyladenosine was used; furthermore, 1 ADO receptor-deficient mice, pretreatment O also increases the vasoconstrictor effect of Additional studies have demonstrated no in cytosolic calcium in ADO-pretreated arter- ut the effect is inhibited by blocking the ADO rt into the cells with nitrobenzyl thioinosine; in e phosphorylation of MAP kinase as well as of regulatory ligh-chain protein (MLC20) were d with the ADO pretreatment. This study s that the ADO effect depends on its transpor- to the cells and phosphorylation of p38 MAPK C20 in vascular smooth muscle cells, as well as effect of ADO independent of calcium and it is mice respo able AT1 is ab analo In an subst tion renal in ele form clam findi In fu ATP back phos locat in th deph gene deph the m [25�] 29,30 respo arter the n may For a [27�] Reg enzy ang II in On infus as w eleva [34�� eleva it wa of A conte tion ische eithe resto value ht © Lippincott Williams & Wilkins. Unauthorized horylate ATP and ADP and may catalyze the ion of AMP. In the NTPDase1-deficient mice horylation of ATP by the enzyme is required for ula densa-dependent regulation of vascular tone he studies mentioned earlier [25�,26,27�,28, 31] point to ADO as the vasoactive compound ible for the contraction present in the afferent , during the activation of TGF and support ion that changes in ADO-metabolizing enzymes involved in the ADO-AngII interaction [27�]. mprehensive review on this topic see reference tion of adenosine-metabolizing es and adenosine receptors by ensin II in the adenosine–angiotensin action basis of the evidence that AngII temporal induces marked renal vasoconstriction [32], as the fact that interstitial AngII is strikingly d [33] under these conditions, Franco et al. ested the hypothesis that AngII was able to the concentrations of intrarenal ADO. Indeed, learly demonstrated that the temporal infusion II was able to elevate interstitial and tissue of ADO [34��]. In this regard, the vasoconstric- duced by AngII suggests that AngII-induced a leads to de-novo formation of ADO, causing additive or modulated vasoconstriction. The ion of glomerular hemodynamics to near-normal by an acute infusion of a specific ADO A1 (8-cyclopentyl-1,3-dipropylxanthine, DPCPX) e TGF is completely inhibited, and the renal e to AngII is significantly reduced [21]. Compar- ults have been obtained in mice with deletions of gII receptors or ADO-converting enzyme: TGF t in these animals and the response to ADO is markedly diminished [22,23]. fort to identify the mediatorof the TGF signal, tial evidence has been obtained of the participa- ADO-metabolizing enzymes in the regulation of eriole vascular tone; initially, Thomson et al. [24], nt micropuncture studies in rats, prevented ADO n by blockade of 50-nucleotidase (50ND) or by g ADO activity at the single nephron level, this strongly suggesting ADO as themediator of TGF. er experiments in the ecto-50ND [23] and ecto- deficient mice [25�], the tubuloglomerular fee- sponse is significantly reduced. Nucleoside tri- te diphosphohydrolase (NTPDase1) has been in the glomeruli, in the renal vasculature and reproduction of this article is prohibited. Copyrigh suggests that the increased local renal ADO concen- tration interacts with AngII. In addition, AngII induced a signifi activity mRNA tration recepto strictor Regula enzym oxide Some st associat ecto-50ND activity [36,37] This is something unexpected as high decreas acute ex elevatio effect o compen increasi Further inhibits nitric ox howeve model of nitra nitric o free rad and thr is possi occur [3 not infl previou needed synergi action u effects metabo Conclu Recent enzyme centrati the alte important role in the ADO-AngII interaction. The renal vasocon formati of ADO Change kidney that me effects; the alteration in ADO receptors further contrib- utes to the synergic interaction between ADO and I. I A e r m no ork al C re of p ighl spe �� of out nal Lite var icroc ll PD 03; einh giot :F2 ielm an ysio var e re var mod yas col udy ts t Ca les. llon v 2 scho ysio shiy cept 14. i EY ntro 06; ng terio ns 2 udy tion ract t art n Y, Garvin JL, Liu R, Carretero OA. Possible mechanism of efferent teriole (ef-Ar) tubuloglomerular feedback. Kidney Int 2007; 71:861– 6. udy release, wh efferent art epto ckso eglo nse nstr rfus 65. 66 Circulation and hemodynamics striction induced by AngII leads to de-novo on of ADO through a decrease in the activity deaminase or, possibly, by increasing 50ND. s in the ADO milieu induced by AngII in the results in an unbalance between ADO receptors diate vasodilation (A2) and vasoconstrictor (A1) A1 rec 14 Ja pr 15 Ha co pe 24 NaCl diet induces volume expansion, as well as a e in renin release and AngII production, at least in periments. In this regard, it is possible that AngII n for a long term could have a direct regulatory n the enzyme or maybe 50ND may increase as a satory mechanism in chronic high NaCl states, ng ADO production to regulate TGF. more, it has been suggested that nitric oxide 50ND in the kidney [37,38]. In acute studies, ide increases to counteract the effect of AngII, r, in chronic states as in the Ang II-infused we have demonstrated that urinary excretion tes falls to near zero at day 14, indicating that xide is consumed by the production of oxygen ical species generated by the AngII infusion ough the NADPH pathway [32]; in addition, it ble that nitrosylation rather than nitration may 7], thus the consumption of nitric oxide would uence 50ND in the AngII-infused model as sly demonstrated [32]. Further studies will be to clarify the mechanisms involved in the c interaction between ADO and AngII inter- nder chronic elevation of AngII, as well as the of NaCl and nitric oxide upon the ADO lizing enzymes. sion studies show that the ADO-metabolizing s participate in the regulation of adenosine con- on in the kidney and tubuloglomerular feedback; ration of ADO-metabolizing enzymes plays an Additio World 1 Na m 2 Be 20 3 W an 26 4 Sp by Ph 5 Na th 6 Na he 7 � Ha ma This st the fac T type arterio 8 Va Re 9 In Ph 10 Ni re F4 11 La co 20 12 � Fe ar te This st modula counte afferen 13 � Re ar 86 This st cant decrease in membrane ADO deaminase , as well as downregulation of protein and of the enzyme. The elevated ADO concen- induced a downregulation of the A2a ADO rs [34��], which allows a predominant vasocon- effect mediated by A1 ADO receptors. tion of adenosine-metabolizing es and adenosine by NaCl and nitric in adenosine–angiotensin II interaction udies have demonstrated that high NaCl diet is ed with higher renal ADO content [35] or higher AngI AngI as th othe Ack This w Nation Refe Papers been h � of t © Lippincott Williams & Wilkins. Unauthorized suggests that increasing cell Ca2þ in the macula densa stimulates ATP ich is hydrolyzed to adenosine, activating A2 ADO receptors in the eriole and inducing vasodilation. In the afferent arteriole ADO activates rs and induces vasoconstriction. n EK, Zhu C, Tofovic SP. Expression of adenosine receptors in the merular microcirculation. Am J Physiol 2002; 283:F41–51. n PB, Castrop H, Briggs J, Schnermann J. Adenosine induces vaso- iction through Gi-dependent activation of phospholipase C in isolated ed afferent arterioles of mice. J Am Soc Nephrol 2003; 14:2457– In addition, independent pathways of ADO or T1 receptors begin to be investigated, as well regulation of ADO-metabolizing enzymes by ediators. wledgements was supported by Grant 79661 (to M. Franco) from the ouncil of Science and Technology (CONACYT), Mexico. nces and recommended reading articular interest, published within the annual period of review, have ighted as: cial interest standing interest references related to this topic can also be found in the Current rature section in this issue (p. 95). LG, Inscho EW, Majid DSA, et al. Paracrine regulation of the renal irculation. Physiol Rev 1996; 76:425–536. , Lapointe JY, Peti-Peterdi J. Macula densa signaling. Annu Rev Physiol 65:481–500. precht H, Lorenz JN, Briggs JP, Schnermann J. Synergistic effects of ensin and adenosine in the renal microvasculature. Am J Physiol 1994; 27–F239. ann WS, Oswald H. Blockade of postoclussive renal vasoconstriction antagonist: evidence of an angiotensin-adenosine interaction. Am J l 1979; 237:F463–F464. LG, Inscho EW, Iming JD, Mitchell KD. Heterogeneous mechanisms in nal microvasculature. Kidney Int 1998; 54 (Suppl 67):S-17–S-21. LG. Integrating multiple paracrine regulators of renal microvascular ynamics. Am J Physiol 1998; 274:F433–F444. hi K, Wakino S, Sugano N, et al. Ca2þ channel subtypes and phar- ogy in the kidney. Cir Res 2007; 100:342–353. describes the renal distribution of Ca2þ channel subtypes, as well as hat L-Type Ca2þchannel blockers induce afferent vasodilation and 2þchannel blockers induce vasodilation in afferent and efferent V, Mu¨hlbauer B, Osswald H. Adenosine and kidney function. Physiol 006; 86:901–940. EW. Modulation of renal microvascular function by adenosine. Am J l 2003; 285:R23–R25. ama A, Inscho EW, Navar LG. Interaction of adenosine A1 and A2a ors on renal microvascular reactivity. Am J Physiol 2001; 280:F406– , Patzak A, Steege A, et al. Contribution of adenosine receptors in the l of arteriolar tone and adenosine-angiotensin II interaction. Kidney Int 70:690–698. MG, Navar LG. Adenosine A2 receptor activation attenuates afferent lar autoregulation during adenosine receptor saturation in rats. Hyper- 007; 50:744–749. demonstrates the interaction between ADO A1 and A2 receptors in the on the afferent tone and autoregulation. The activation of A2 receptors s the effect of A1 receptors leading to vasodilation and decrease in eriolar autoregulatory efficiency. reproduction of this article is prohibited. Copyrig 16 �� Hansen PB, Friis UG, Uhrenholt TR, et al. Intracellular signaling pathways in the vasoconstrictor responses of mouse afferent arterioles to adenosine. Acta Physiol 2007; 191:89–97. This is a comprehensive study of the intracellular signaling pathways by which ADO causes renal arteriolar constriction. 17 �Metha PK, Griendling KK. Angiotensin II cell signaling: physiological and pathological effects in the cardiovascular system. Am J Physiol 2007; 292:C82–C97. This is a complete review of the cell signaling of all the effects induced by activation of Ang II AT1 receptors. 18 Feng M-G, Navar LG. Angiotensin II-mediated constriction of afferent and efferent arterioles involves T-type Ca2þ channel activation. Am J Nephrol 2004; 24:641–648. 19 Lai EY, Martinka P, Fa¨hling M, et al. Adenosine restores angiotensin II-induced contractions by receptor-independent enhancement of calcium sensitivity in renal arterioles. Circ Res 2006; 99:1117–1124. 20 �� Patzak A, Lai EY, Fahling M, et al. Adenosine enhances long term the contractile response to angiotensin II in afferent arterioles. Am J Physiol 2007; 293:R2232–R2242. This study suggests a long-term effect of extracellular adenosine on the angio- tensin II-mediated constriction of afferent arterioles. The ADO effects depend on the transportation of the nucleoside into the cell, do not require mediation by ADO receptors and activate p38 MAP kinase. 21 Hansen PB, Hashimoto S, Briggs J, Schnermann J. Attenuated renovascular constrictor response to angiotensin in adenosine 1 receptor Knockout mice. Am J Physiol 2003; 285:R44–R49. 22 Traynor T, Yang T, Yuning G, et al. Inhibition of adenosine-1 receptor- mediated preglomerular vasoconstriction in AT1A receptor deficient mice. Am J Physiol 1998; 275:F922–F927. 23 Huang DG, Vallon V, Zimmerman H, et al. Ecto-50-nucleotidase (cd73)- dependent and independent generation of adenosine participates in the mediation of tubuloglomerular feedback in vivo. Am J Physiol 2006; 291:F282–F288. 24 Thoms tidase 298. 25 � Schne from g A compreh corroborate involved in eliciting aff 26 Castro feedba Clin In 27 � Opperman M, Fridman DJ, Faulhaber-Walter R, et al. Tubuloglomerular feed- back and renin secretion in NTPDase 1/CD39-deficient mice. Am J Physiol 2008; 294:F965–F970. This study demonstrates that, in NTPDase/CD39-deficient mice an extacellular dephosphorylation cascade, during tubular-vascular signal transmission is initiated by regulated release of ATP form macula densa cells, resulting in adenosine- mediated afferent arteriole constriction. 28 Schnermann J, Levine DZ. Paracrine factors in tubuloglomrular feedback: adenosine, ATP, and nitric oxide. Ann Rev Physiology 2003; 65:501–529. 29 Inscho EW. Modulation of renal microvascular function by adenosine. Am J Physiol 2003; 285:R23–R25. 30 �� Castrop H. Mediators of tubuloglomerular feedback regulation of glomerular filtration: ATP and adenosine. Acta Physiol 2007; 189:3–14. This is a comprehensive review of the effects of ATP and ADO as mediators of the tubuloglomerular feedback mechanism, as we as the possible release of ATP from the macula densa, extracellular degradation of ATP to ADO by ecto-50ND as an important regulator of ADO production, and the final step, ADO-mediated vaso- constriction of the afferent arteriole. 31 Nishiyama A, Navar LG. ATP mediates tubuloglomerular feedback. Am J Physiol 2002; 283:R273–R275. 32 Franco M, Tapia E, Santamarı´a J, et al. Renal cortical vasoconstriction contributes to the development of salt sensitive hypertension after angiotensin II exposure. J Am Soc Nephrol 2001; 12:2263–2271. 33 Zou LX, Hymel A, Iming JD, Navar LG. Renal acumulation of circulating antiotensin II in the angiotensin II-infused rats. Hypertens 1996; 27:658–662. 34 �� Franco M, Bautista R, Pe´rez-Mendez H, et al. Renal interstitital adenosine is increased in angiotensin II-induced hypertensive rats. Am J Physiol 2008; 294:F84–F92. This study describes how AngII is able to decrease the activity of ADO deaminase, leading to an increase in interstitial renal ADO concentration, which induces downregulation of ADO A2a receptors; as a consequence, an imbalance between A1 and A2 receptors is responsible for the marked renal vasoconstriction observed. In this model, the full effects of AngII are exerted after several days; the AngII-ADO interaction in vivo is clearly demonstrated. ragy HM, Linden J. Sodium intake markedly alters interstitial fluid adenosine. per u A etab per tria ric o ysio egfr ide 1:4 Angiotensin II–adenosine interaction in the kidney Franco et al. 67 rmann J, Briggs JP. Tubuloglomerular feedback: mechanistic insights ene-manipulated mice. Kidney Int 2008; 74:418–426. ensive review of the evidence obtained in genetically altered mice that the data obtained by micropunction studies about the mechanism the function of TGF, as well as the importance of ADO and AngII erent arteriole vasoconstriction. p H, Huang Y, Hashimoto S, et al. Impairment of tubuloglomerular ck regulation of GFR in ecto-50-nucleotidase/CD73-deficient mice. J vest 2004; 114:634–642. Hy 36 Zo m Hy 37 Sa nit Ph 38 Si ox 27 ht © Lippincott Williams & Wilkins. Unauthorized tension 1996; 27:404–407. -P, Feng W, Li P-L, Cowley AW. Effect of salt loading on adenosine olism and receptor expression in renal cortex and medulla in rats. tension 1999; 33:511–516. no J, Wead L, Cardus A, et al. Regulation of 50-nucleotidse by NaCl and xide: potential roles in tubuloglomerular feedback and adaptation. Am J l 2006; 291:F1078–F1082. ied G, Amiel C, Friedlander G. Inhibition of Ecto-5-nucleotidase by nitric donors. Implications in renal epithelial cells. J Biol Chem 1996; 659–4664. on S, Bao D, Deng A, Vallon V. Adenosine formed by 50-nucleo- mediates tubuloglomerular feedback. J Clin Invest 2000; 106:289– 35 Si reproduction of this article is prohibited. Interaction of intrarenal adenosine and angiotensin II in kidney vascular™resistance Introduction Regulation of vascular tone Regulation of vascular tone by adenosine Regulation of vascular tone by angiotensin II Synergic interaction between adenosine and angiotensin II Regulation of adenosine-metabolizing enzymes and adenosine receptors by angiotensin II in the adenosine-angiotensin II interaction Regulation of adenosine-metabolizing enzymes and adenosine by NaCl and nitric oxide in adenosine-angiotensin II interaction Conclusion Acknowledgements References and recommended reading
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