Modulation of renal microvascular function by adenosine

EDITORIAL FOCUSModulation of renal microvascular function by adenosineEdward W. InschoEdward W. InschoDepartment of Physiology, Medical College of Georgia, Augusta, Georgia 30912-3000Published Online:01 Jul 2003https://doi.org/10.1152/ajpregu.00181.2003MoreSectionsPDF (49 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations renal damage, as a consequence of hypertension, is well established. Chronic elevation of arterial blood pressure results in a steady decline in the number of functional glomeruli, leading to a reduction in renal filtering capacity (6, 19, 23). Evidence indicates that a significant portion of hypertension-associated renal damage occurs as a consequence of inappropriately low preglomerular resistance, allowing glomerular capillary pressure to rise above normal (6, 34). Direct assessment of afferent arteriolar responses to elevations in renal perfusion pressure clearly demonstrates impaired autoregulatory capability in kidneys from hypertensive rats compared with kidneys from normotensive controls (2, 5, 10–12, 14, 16, 27, 33). Impairment of autoregulatory capability reflects an intrinsic change within the kidney of hypertensive animals, because autoregulatory behavior was not restored by perfusion with blood from normotensive donors and thus could not be attributed to a humoral factor present in the blood of hypertensive donors (14). Therefore, chronic elevation of arterial pressure produces a functional alteration in the afferent arteriole or in arteriolar signaling pathways, which reduces or abolishes autoregulatory control of glomerular capillary pressure. This phenomenon cannot be attributed to a generalized reduction in preglomerular responsiveness to vasoactive stimuli, because many investigators have reported exaggerated responsiveness to vasoactive agents such as angiotensin II, norepinephrine, and endothelin (12, 27). Pathological alterations in the actions or release of locally generated regulators of vascular resistance have not been heavily investigated but do represent a significant target for explaining inappropriate renal vascular control.Regulation of renal blood flow and renal vascular resistance is accomplished by the interaction of numerous intrarenal and extrarenal influences (27). Certainly ambient blood pressure, sympathetic nerve activity, and circulating vasoactive substances are major extrarenal determinants. However, the kidney produces a multitude of locally generated substances, including ATP, adenosine, and angiotensin II, that also contribute to the regulation of renal vascular resistance (1, 13, 18, 24, 26, 27, 37, 45). As these influences converge on the renal vasculature, their respective contributions primarily focus on setting preglomerular resistance. The afferent arteriole is the primary resistance element responsible for controlling glomerular capillary pressure and accounts for between 80 and 90% of renal vascular resistance. Exactly how locally produced vasoactive substances regulate afferent arteriolar function continues to be clarified. Significant roles are emerging for constitutive contributions by the tissue renin angiotensin system (26), cytochrome P-450 metabolites of arachidonic acid (24, 32), release of nitric oxide and products of oxidative stress by endothelium and tubular epithelia (5, 27, 44, 45), local activation of the P2 receptor system by paracrine release of ATP (1, 13, 29), and the regional influences of the ubiquitous product of tissue metabolism, adenosine (3, 37, 40). Although the relative importance of each of these systems is still enthusiastically debated, there is a general consensus that each plays an important physiological role in setting ambient renal vascular resistance. Furthermore, the potential exists for more sophisticated levels of regulatory control, when one considers the impact of complex interactions between these systems and pathways.A major property by which the kidney sets and regulates glomerular capillary pressure and renal blood flow is known as autoregulation. Autoregulatory control is intrinsic to the kidney and functions in the absence of sympathetic nerve activity and in the absence of blood and circulating vasoactive substances. It is a collective manifestation of myogenic influences, inherent to all vascular smooth muscle, and the added level of control contributed by the tubuloglomerular feedback mechanism. Together, they control preglomerular resistance and thus glomerular hemodynamics. Today, the major hypotheses offered to explain the mechanisms of autoregulatory control center on P2X receptor activation by ATP (1, 13, 30) and A1 receptor activation by adenosine (3, 36, 37, 40). The most recent evidence in support of these respective hypotheses comes from the work of Bell and colleagues (1). In those studies, initiation of tubuloglomerular feedback (TGF) responses by macula densa cells was associated by ATP release from the basolateral surface via activation of a large-conductance anion channel. In a more recent report, Inscho et al. (15) reported that mice lacking P2X1 receptors exhibit impaired autoregulatory responses but retain responsiveness to adenosine (15). The alternative hypothesis is supported by two recent reports that mice lacking adenosine-sensitive A1 receptors also lack TGF responses (3, 40). This topic was debated in a series of opinion articles printed in this publication (30, 36).Regardless of the identity of the signaling molecules responsible for autoregulatory adjustments in afferent arteriolar resistance, adenosine remains an important modulator of renal microvascular function. There is clear evidence for the involvement of A1 and A2a receptors in renal function (17, 25, 27, 35); however, the role of A2b and A3 receptors in regulating renal vascular and tubular function is less clear. The renal vasculature expresses both A1 and A2a receptors, and both likely participate in regulating renal microvascular function (17, 25, 27, 35). Different tubular segments also express adenosine receptors where they may affect regulation of tubular transport (17, 25, 27, 35). The influence of adenosine on renal hemodynamics is complex. Typically, intrarenal infusion of adenosine results in a transient reduction in renal blood flow followed by a sustained increase (17, 20, 25, 27, 35). It is believed that the initial renal vasoconstriction involves activation of preglomerular A1 receptors followed by a postglomerular vasodilation, mediated by A2 receptors (17). Indeed, the prevailing view is that vasodilation of the postglomerular circulation, particularly in the inner cortex, redistributes blood flow from the cortex to the medulla (8, 21, 22, 38, 42). Direct appraisal of microvascular function, however, corroborates only the preglomerular A1 receptor-mediated vasoconstriction and does not substantiate postulated vasodilation of postglomerular vessels. Two reports evaluated efferent arteriolar responses to adenosine in the inner cortex (4, 28). In both studies, 10 μM adenosine vasoconstricted juxtamedullary afferent and efferent arterioles. Greater adenosine concentrations reversed the vasoconstriction and returned arteriole diameters to near control values. Selective blockade of A1 receptors with KW-3902 resulted in marked adenosine-mediated vasodilation of afferent and efferent arterioles, whereas selective blockade of A2a receptors with KW-17837 significantly augmented adenosine-mediated vasoconstriction in both arteriolar segments (28). These data demonstrate that vasoconstriction is the principal response evoked by adventitial administration of adenosine to afferent and efferent arterioles of the inner cortex and are at variance with the postulate that adenosine vasodilates the inner cortical microvasculature. It should be noted, however, that adenosine may provide an important vasodilatory influence in the medullary circulation. Zou et al. (46) reported that blockade of medullary A2 receptors, with the A2 receptor antagonist 3,7-dimethyl-1-propargylxanthine (DMPX) decreased outer and inner medullary blood flow, as measured using laser-Doppler flowmetry. In contrast, A1 receptor blockade with 8-cyclopentyl-1, 3-dipropylxanthine (DPCPX) or A3 receptor blockade with N6-benzyl-5′-(N-ethylcarbonxamido)adenosine left medullary blood flow unchanged. Thus, whereas the inner cortical microvasculature does not exhibit adenosine-mediated vasodilation until A1 receptors are blocked, or until local adenosine concentration exceeds 10 μM, it is possible that resistance elements of the medullary circulation respond to endogenous adenosine with A2 receptor-mediated vasodilation.Investigations into the mechanisms by which adenosine influences renal vascular resistance have led to the speculation that a significant interaction exists between adenosine and angiotensin II (4, 7, 9, 31, 39, 41). A1 receptor blockade with DPCPX significantly reduced angiotensin II-mediated vasoconstriction of isolated rabbit afferent arterioles (43). Whole kidney studies suggest that ambient adenosine concentrations preset renal microvascular reactivity and modulate preglomerular responsiveness to angiotensin II (9). More recent studies using mice deficient in AT1A receptors, reveal that adenosine-mediated preglomerular vasoconstriction is markedly attenuated compared with heterozygote or wild-type mice (41). Finally, in this issue of the American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, Hansen et al. (9a) report that chronic deficiency of the adenosine A1 receptor modestly attenuates the ability of angiotensin II to vasoconstrict renal resistance vessels. This basic observation was obtained using whole kidney approaches as well as isolated afferent arterioles from wild-type and A1 receptor-knockout mice. These observations are consistent with an interaction between adenosine and angiotensin to regulate preglomerular vascular resistance. However, not all studies support such an interaction. Direct assessment of microvascular responses to angiotensin II indicates that preglomerular vasoconstriction can occur independent of adenosine receptor activation (7). A1 receptor blockade with DPCPX had no significant effect on angiotensin II-mediated vasoconstriction of afferent or efferent arterioles (7). Furthermore, no significant interaction was found in studies evaluating the role of endogenous adenosine to serve as an essential cofactor in facilitating angiotensin II-mediated vasoconstriction of juxtamedullary afferent or efferent arterioles (4). In those studies, pharmacological blockade of adenosine receptors or exposure to exogenous adenosine did not alter angiotensin II-mediated vasoconstrictor responses compared with untreated control kidneys. Taken together, the issue of whether or not the renal microvascular response to angiotensin II and adenosine is significantly, or importantly, altered by an interaction between the angiotensin and the purine nucleoside adenosine remains unresolved. References 1 Bell PD, Lapointe JY, Sabirov R, Hayashi S, and Okada Y. Macula densa cell signaling involves ATP release through a maxi anion channel. Proc Natl Acad Sci USA 100: 4322–4327, 2003.Crossref | PubMed | ISI | Google Scholar2 Bouriquet N and Casellas D. Chronic l-NAME hypertension in rats and autoregulation of juxtamedullary preglomerular vessels. Am J Physiol Renal Fluid Electrolyte Physiol 269: F190–F197, 1995.Link | ISI | Google Scholar3 Brown R, Ollerstam A, Johansson B, Skott O, Gebre-Medhin S, Fredholm B, and Persson AEG. Abolished tubuloglomerular feedback and increased plasma renin in adenosine A1 receptor-deficient mice. Am J Physiol Regul Integr Comp Physiol 281: R1362–R1367, 2001.Link | ISI | Google Scholar4 Carmines PK and Inscho EW. Renal arteriolar angiotensin responses during varied adenosine receptor activation. Hypertension 23: I-114–I-119, 1994.Crossref | PubMed | ISI | Google Scholar5 Carmines PK, Inscho EW, Ortenberg JM, and Cook AK. Determinants of renal microvascular autoregulatory behavior in normal and hypertensive rats. Kidney Int 39, Suppl 32: S-89–S-93, 1991.ISI | Google Scholar6 Cutler JA. High blood pressure and end-organ damage. J Hypertens 14: S3–S6, 1996.ISI | Google Scholar7 Dietrich MS, Endlich K, Parekh N, and Steinhausen M. Interaction between adenosine and angiotensin II in renal microcirculation. Microvasc Res 41: 275–288, 1991.Crossref | PubMed | ISI | Google Scholar8 Dinour D and Brezis M. Effects of adenosine on intrarenal oxygenation. Am J Physiol Renal Fluid Electrolyte Physiol 261: F787–F791, 1991.Link | ISI | Google Scholar9 Hall JE and Granger JP. Adenosine alters glomerular filtration control by angiotensin II. Am J Physiol Renal Fluid Electrolyte Physiol 250: F917–F923, 1986.Link | ISI | Google Scholar9a Hansen PB, Hashimoto S, Briggs J, and Schnermann J. Attenuated renovascular constrictor responses to angiotensin II in adenosine 1 receptor knockout mice. Am J Physiol Regul Integr Comp Physiol 285: R44–R49, 2003.Link | ISI | Google Scholar10 Hayashi K, Epstein M, and Saruta T. Altered myogenic responsiveness of the renal microvasculature in experimental hypertension. J Hypertens 14: 1387–1401, 1996.Crossref | PubMed | ISI | Google Scholar11 Hutchins PM, Lynch CD, Cooney PT, and Curseen KA. The microcirculation in experimental hypertension and aging. Cardiovasc Res 32: 772–780, 1996.Crossref | PubMed | ISI | Google Scholar12 Imig JD and Inscho EW. Adaptations of the renal microcirculation to hypertension. Microcirculation 9: 315–328, 2002.Crossref | PubMed | ISI | Google Scholar13 Inscho EW. P2 receptors in the regulation of renal microvascular function. Am J Physiol Renal Physiol 280: F927–F944, 2001.Link | ISI | Google Scholar14 Inscho EW, Carmines PK, Cook AK, and Navar LG. Afferent arteriolar responsiveness to altered perfusion pressure in renal hypertension. Hypertension 15: 748–752, 1990.Crossref | PubMed | ISI | Google Scholar15 Inscho EW, Cook AK, Imig JD, Vial C, and Evans RJ. Pressure-induced autoregulatory responses are inhibited in mice lacking P2X1 receptors (Abstract). FASEB J 17: A103, 2003.Crossref | PubMed | ISI | Google Scholar16 Inscho EW, Imig JD, Deichmann PC, and Cook AK. Candesartan-cilexetil protects against loss of autoregulatory efficiency in angiotensin II infused rats. J Am Soc Nephrol 10: S178–S183, 1999.PubMed | ISI | Google Scholar17 Jackson EK. P1 and P2 receptors in the renal system. In: Handbook of Experimental Pharmacology. New York: Springer-Verlag, 2001, p. 33–71.Google Scholar18 Jackson EK, Mi ZC, Gillespie DG, and Dubey RK. Metabolism of cAMP to adenosine in the renal vasculature. J Pharmacol Exp Ther 283: 177–182, 1997.PubMed | ISI | Google Scholar19 Lahera V, Navarro-Cid J, Cachofeiro V, García-Estañ J, and Ruilope LM. Nitric oxide, the kidney, and hypertension. Am J Hypertens 10: 129–140, 1997.Crossref | PubMed | ISI | Google Scholar20 Le Hir M and Kaissling B. Distribution and regulation of renal ecto-5′-nucleotidase: implications for physiological functions of adenosine. Am J Physiol Renal Fluid Electrolyte Physiol 264: F377–F387, 1993.Link | ISI | Google Scholar21 Levens N, Beil M, and Jarvis M. Renal actions of a new adenosine agonist CGS 21680A, selective for the A2 receptor. J Pharmacol Exp Ther 257: 1005–1012, 1991.PubMed | ISI | Google Scholar22 Levens N, Beil M, and Schulz R. Intrarenal actions of the new adenosine agonist CGS 21680A, selective for the A2 receptor. J Pharmacol Exp Ther 257: 1013–1019, 1991.PubMed | ISI | Google Scholar23 Lundie MJ, Friberg P, Kline RL, and Adams MA. Long-term inhibition of the renin-angiotensin system in genetic hypertension: analysis of the impact on blood pressure and cardiovascular structural changes. J Hypertens 15: 339–348, 1997.Crossref | PubMed | ISI | Google Scholar24 Maier KG and Roman RJ. Cytochrome P450 metabolites of arachidonic acid in the control of renal function. Curr Opin Nephrol Hypertens 10: 81–87, 2001.Crossref | PubMed | ISI | Google Scholar25 McCoy DE, Bhattacharya S, Olson BA, Levier DG, Arend LJ, and Spielman WS. The renal adenosine system: structure, function and regulation. Semin Nephrol 13: 31–40, 1993.PubMed | ISI | Google Scholar26 Navar LG, Harrison-Bernard LM, Nishiyama A, and Kobori H. Regulation of intrarenal angiotensin II in hypertension. Hypertension 39: 316–322, 2002.Crossref | PubMed | ISI | Google Scholar27 Navar LG, Inscho EW, Majid DSA, Imig JD, Harrison-Bernard LM, and Mitchell KD. Paracrine regulation of the renal microcirculation. Physiol Rev 76: 425–536, 1996.Link | ISI | Google Scholar28 Nishiyama A, Inscho EW, and Navar LG. Interactions of adenosine A1 and A2a receptors on renal microvascular reactivity. Am J Physiol Renal Physiol 280: F406–F414, 2001.Link | ISI | Google Scholar29 Nishiyama A, Majid DSA, Taher KA, Miyatake A, and Navar LG. Relation between renal interstitial ATP concentrations and autoregulation-mediated changes in renal vascular resistance. Circ Res 86: 656–662, 2000.Crossref | PubMed | ISI | Google Scholar30 Nishiyama A and Navar LG. ATP mediates tubuloglomerular feedback. Am J Physiol Regul Integr Comp Physiol 283: R273–R275, 2002.Link | ISI | Google Scholar31 Osswald H, Schmitz HJ, and Heidenreich O. Adenosine response of the rat kidney after saline loading, sodium restriction and hemorrhagia. Pflügers Arch 357: 323–333, 1975.Crossref | PubMed | ISI | Google Scholar32 Roman RJ. P-450 metabolites of arachidonic acid in the control of cardiovascular function. Physiol Rev 82: 131–185, 2002.Link | ISI | Google Scholar33 Roman RJ and Kaldunski ML. Renal cortical and papillary blood flow in spontaneously hypertensive rats. Hypertension 11: 657–663, 1988.Crossref | PubMed | ISI | Google Scholar34 Safar ME, Van Bortel LMAB, and Struijker-Boudier HAJ. Resistance and conduit arteries following converting enzyme inhibition in hypertension. J Vasc Res 34: 67–81, 1997.Crossref | PubMed | ISI | Google Scholar35 Schnermann J. Juxtaglomerular cell complex in the regulation of renal salt excretion. Am J Physiol Regul Integr Comp Physiol 274: R263–R279, 1998.Link | ISI | Google Scholar36 Schnermann J. Adenosine mediates tubuloglomerular feedback. Am J Physiol Regul Integr Comp Physiol 283: R276–R277, 2002.Link | ISI | Google Scholar37 Schnermann J and Levine DZ. Paracrine factors in tubuloglomerular feedback: adenosine, ATP and nitric oxide. Annu Rev Physiol 65: 501–529, 2003.Crossref | PubMed | ISI | Google Scholar38 Spielman WS, Britton SL, and Fiksen-Olsen MJ. Effect of adenosine on the distribution of renal blood flow in dogs. Circ Res 46: 449–456, 1980.Crossref | PubMed | ISI | Google Scholar39 Spielman WS and Osswald H. Blockade of postocclusive renal vasoconstriction by an angiotensin II antagonist: evidence for an angiotensin interaction. Am J Physiol Renal Fluid Electrolyte Physiol 237: F463–F467, 1979.Link | ISI | Google Scholar40 Sun DQ, Samuelson LC, Yang TX, Huang YN, Paliege A, Saunders T, Briggs J, and Schnermann J. Mediation of tubuloglomerular feedback by adenosine: Evidence from mice lacking adenosine A1 receptors. Proc Natl Acad Sci USA 98: 9983–9988, 2001.Crossref | PubMed | ISI | Google Scholar41 Traynor T, Yang TX, Huang YG, Arend L, Oliverio MI, Coffman T, Briggs JP, and Schnermann J. Inhibition of adenosine-1 receptor-mediated preglomerular vasoconstriction in AT1A receptor-deficient mice. Am J Physiol Renal Physiol 275: F922–F927, 1998.Link | ISI | Google Scholar42 Ueda J. Adenine nucleotides and renal function: special reference with intrarenal distribution of blood flow. Jpn J Pharmacol 22: 5, 1972.Crossref | Google Scholar43 Weihprecht H, Lorenz JN, Briggs JP, and Schnermann J. Synergistic effects of angiotensin and adenosine in the renal microvasculature. Am J Physiol Renal Fluid Electrolyte Physiol 266: F227–F239, 1994.Link | ISI | Google Scholar44 Welch WJ, Wilcox CS, and Thomson SC. Nitric oxide and tubuloglomerular feedback. Semin Nephrol 19: 251–262, 1999.PubMed | ISI | Google Scholar45 Wilcox CS. Reactive oxygen species: role in blood pressure and kidney function. Curr Hypertens Rep 4: 160–166, 2002.Crossref | PubMed | ISI | Google Scholar46 Zou AP, Nithipatikom K, Li PL, and Cowley AW. Role of renal medullary adenosine in the control of blood flow and sodium excretion. Am J Physiol Regul Integr Comp Physiol 276: R790–R798, 1999.Link | ISI | Google ScholarAUTHOR NOTES Address for reprint requests and other correspondence: E. W. Inscho, Dept. of Physiology, Medical College of Georgia, 1120 15th St., Augusta, GA 30912-3000 (E-mail: [email protected]). 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