Angiotensin II–Induced Reactive Oxygen Species and the Kidney
Anja Sachse and
Gunter Wolf
Department of Medicine, University of Jena, Jena, Germany
Correspondence: Dr. Gunter Wolf, Klinik für Innere Medizin III, University of Jena, Erlanger Allee 101, D-07347 Jena, Germany. Phone: +49-3641-9324301; Fax: +49-3641-9324302; E-mail: gwolf{at}med.uni-jena.de
Angiotensin II (AngII) is an important mediator in renal injury.Accumulating evidence suggests that AngII stimulates intracellularformation of reactive oxygen species (ROS) such as the superoxideanion and hydrogen peroxide. AngII activates several subunitsof the membrane-bound multicomponent NAD(P)H oxidase and alsoincreases ROS formation in the mitochondria. Some of these effectsmay be induced by aldosterone and not directly by AngII. Thesuperoxide anion and hydrogen peroxide influence other downstreamsignaling pathways, such as transcription factors, tyrosinekinases/phosphatases, ion channels, and mitogen-activated proteinkinases. Through these signaling pathways, ROS have distinctfunctional effects on renal cells. They are transducers of cellgrowth, apoptosis, and cell migration and affect expressionof inflammatory and extracellular matrix genes. For example,AngII-mediated expression of p27Kip1, a cell-cycle regulatoryprotein, and induction of tubular hypertrophy depend on thegeneration of ROS. The effects of ROS generated within differentrenal cells ultimately depend on the locally generated concentrationsand the balance of pro- and antioxidant pathways. Although theconcept that AngII mediates oxidative stress in the kidney hasbeen validated in experimental models, the exact role is stillincompletely understood in human renal diseases.
The renin-angiotensin-aldosterone system (RAAS) plays a pivotalrole in regulating physiologic and pathophysiologic processesin the kidney.1 Although different components of the RAAS, suchas renin, aldosterone, and various angiotensin fragments, caninitiate renal impairment on their own, angiotensin II (AngII)is the primary effector of this system. AngII was originallyidentified as a vasoconstrictor and potent stimulus of aldosteronerelease from the suprarenal glands and also has been implicatedin the regulation of glomerular filtration and tubular transport.Intensive research in the past 15 yr has provided convincingevidence that AngII is a key contributor to progression of renaldisease by stimulating growth, inflammation, and fibrosis ofthe kidney.2
AngII binds to specific receptors to mediate its particulareffects. The angiotensin type 1 (AT1) and type 2 (AT2) receptorsare the best characterized receptors on a molecular level, butadditional types may exist. Most of the known physiologic andpathophysiologic effects of AngII are transduced by the AT1receptor, a 359–amino acid protein that belongs to theseven-membrane superfamily of G-protein–associated receptors.3After the binding of AngII to the AT1 receptors, a series ofsignaling cascades is activated. Although traditionally dividedinto G-protein–and non–G-protein–related signaling,there are so many interactions between these subgroups of AngII-inducedsignaling pathways that a strict distinction becomes difficult.An example of a G-protein–dependent pathway is activationof phospholipase C with the subsequent production of inositol1,4,5-phosphate and diacylglycerol. Non–G-protein pathwaysinduced by AngII are phosphorylation and the activation of varioustyrosine kinases. AngII is an important mediator of oxidativestress, and reactive oxygen species (ROS) induced by AngII arechief signal intermediates in several signal transduction pathwaysinvolved in renal pathophysiology.4 Moreover, AngII-inducedROS are important for renal growth processes, inflammation,and fibrosis.5 This brief review highlights how AngII stimulatesROS formation and how ROS contribute to kidney injury.
ROS are composed of a series of oxygen intermediates, includingthe free radical superoxide anion (·O2–), the nonradicalhydrogen peroxide (H2O2), the highly reactive hydroxyl freeradical (·OH), peroxynitrite (ONOO–), and singletoxygen (1O2), in which one of the electrons is raised to anorbital of higher energy with an inversion of spin. Some ofthe pathways for generation and metabolism of ROS are shownin Figure 1. The original source is O2, which is univalentlyreduced to form ·O2– by multiple enzymatic pathways(Figure 1). ·O2– is unstable in aqueous solutionswith a half-life of seconds.6–10 It is catalyzed intoH2O2 by superoxide dismutase. This relatively weak oxidant holdsa central position in the further metabolism to other ROS. H2O2can oxidize chloride to form the reactive hypochlorous acid(HOCl) in cells that express the enzyme myeloperoxidase. HOClmay further react with O2– to form the hydroxyl free radical(HOCl + ·O2– ·OH + O2 + Cl–). Alternatively,hypochlorite (OCl–) can further interact with H2O2 toproduce singlet oxygen (OCl– + H2O21O2 + H2O + Cl–).·OH can also be formed from H2O2 and ·O2–by an iron-catalyzed reaction, the so-called Haber-Weiss reaction.6,10It is interesting that the Haber-Weiss reaction is also implicatedin the generation of 1O2.
Figure 1. Overview of enzymatic systems generating ROS such as ·O2–. In quantitative terms, mitochondrial oxidative phosphorylation is presumably the most important system, but NAD(P)H oxidase is pivotal for AngII-mediated ROS formation. ·O2– is unstable and is catalyzed into H2O2 by superoxide dismutase (SOD). H2O2 has a primary role in the further metabolism of other ROS. H2O2 can oxidize chloride to form the reactive hypochlorous acid (HOCl) in the presence of myeloperoxidase (MPO). The highly reactive hydroxyl radical (·OH) can also be formed from H2O2. Alternatively, ·O2– is detoxified by catalase to H2O.
In addition, there are several interactions between ROS andnitric oxide (NO) leading to a decrease in NO bioavailability.8,11·O2– rapidly reacts with NO, yielding ONOO–,which may decompose into nitrate and ·OH. ONOO–also oxidizes the zinc-thiolate center of NO synthase (NOS),resulting in a decrease in NO formation.8 H2O2 reacts with theheme center of myeloperoxidase to produce FeIV that, in turn,oxidizes NO to NO2–.9,12 Another interaction between ROSand NO is the oxidation of the NOS co-factor tetrahydrobiopterin(BH4). In the absence of BH4, the NOS rather forms O2–instead of NO, a process called NO uncoupling, leading to increasedoxidative stress.13,14 Finally, ROS induce lipid and proteinoxidation, generating various further active compounds suchas lipid peroxyl (·LOO) and lipid alkoxyl radicals (·LO).15–17
Because of the highly reactive nature of ROS with the potentialof deleterious effects on cell integrity, ROS must be neutralizedby protective enzymes and endogenous antioxidants (Figure 1).Because H2O2 is less reactive than ·O2–, superoxidedismutase may be considered as part of a detoxification pathwayneutralizing superoxide anions.12 Furthermore, H2O2 is reducedby catalase or glutathione peroxidase to H2O. In particular,the tetrameric glutathione peroxidase serves as a detoxificationpathway for several noxious lipid peroxides.
The key initial step in the formation of all ROS is the conversionof molecular O2 into ·O2–. Several enzymatic pathwayscan generate ·O2– (Figure 1), but in overall quantitativeterms, it is the electron transport chain in mitochondria thatis the most important source. For AngII-mediated ROS generation,the NAD(P)H oxidase is the central enzyme complex.11,12
The "classic" NAD(P)H oxidase is an enzymatic complex that isresponsible for the generation of ·O2– in neutrophilsduring the respiratory burst.13 Under normal conditions, theprototypic neutrophil NAD(P)H oxidase is dormant in nonactivatedneutrophils with only two subunits, glycoprotein (gp)91phox(for phagocyte oxidase) and p22phox, comprising the membrane-boundcytochrome b558 (Figure 2). The flavoprotein FAD is a co-factorlinking NADPH and cytochrome b558. Two isoforms of the smallGTP-binding protein Rac, Rac1 and Rac2, promote the assemblyof the NAD(P)H oxidase multienzyme complex and may act as aswitch that triggers the electron transport.18 Rac2 exhibitsa high affinity for cytochrome b558 and seems to be constitutivelyassociated with the cell membrane. During the respiratory burstand cellular activation, the additional components p67phox,p47phox, p40phox, and Rac1 shift from the cytosol to the membrane(Figure 2). These proteins bind to the poly-l-proline–richdomain of p22phox through the interaction of the src homologydomain-3 (SH3). Furthermore, the SH3-mediated interaction inducesthe combination of p67phox with p47phox. The translocation activatesthe NAD(P)H oxidase to generate large amounts of ·O2–(approximately 10 nmol/min per 106 cells) in the extracellularenvironment.18
Figure 2. The multienzyme complex that constitutes neutrophil NAD(P)H oxidase. The subunits Rac1/2, p67phox, p47phox, and p40phox reside under normal conditions in the cytosol and associate with the membrane-bound Nox/p22phox subunits only after activation. p47phox interacts with components of the cytoskeleton. In different cell types, different Nox subunits1,2,4 associate with p22phox. AngII stimulates transcription of different NAD(P)H oxidase subunits such as p22phox and p47phox or various Nox proteins. In addition, AngII stimulation results in activation of the enzyme complex by association of the subunits. The associated enzyme complex generates ·O2–.
Although all components of the classic neutrophil NAD(P)H oxidaseare also found in nonphagocytic cells (e.g., in endothelialcells), there are several important structural and functionaldifferences.19,20 Nonphagocytic NAD(P)H oxidase enzymes continuouslygenerate low levels of ·O2– intracellularity andcan be further stimulated by several agonists, including AngII.In fact, there is evidence that several of the subunits arefully preassembled intracellularly in a perinuclear distributionassociated with the cytoskeleton.21 Moreover, at least fiveisoforms of gp91phox, named Nox1 through 5, have been characterized,whereas the classic neutrophil isoform gb91phox was renamedNox2.18 Nox1 and 3 through 5 are expressed in nonphagocyticcells. In the kidney, all components of the neutrophil NAD(P)Hoxidase including Nox2 are present in endothelial cells.19,20–23In addition, Nox4 is widely expressed in renal cells, and p47phoxis strongly expressed in glomeruli. In colonic epithelial cells,homologues of p47phox and p67phox (NOXO 1 and NOXA1) are found,but an expression in renal cells has not yet been studied. Thereare also structural differences, and Nox5 does not require p22phoxas a docking module, whereas Nox4 operates constitutively, notrequiring cytosolic subunits.
More than a decade ago, it was concluded from indirect evidencethat AngII may induce ROS formation.24 Acute AngII infusionexperiments into naive rats in the presence or absence of variousfree radical scavengers were performed, and these scavengerspartly inhibited vascular hyperpermeability and cellular damage.22,23Subsequent studies demonstrated that treatment of cultured vascularsmooth muscle cells with AngII for 4 to 6 h increased ·O2–.25–27These effects were mediated by the AT1 receptor and were inducedby an activation of membrane-bound NAD(P)H oxidase because theflavoprotein inhibitor diphenylene iodinium and p22phox antisenseoligonucleotides attenuated this response.27–30 AT1 receptor–transducedROS formation, depending on NAD(P)H oxidase, has also been observedin several renal cells in culture.27 Similar observations havebeen made in the kidney when the endogenous renin-angiotensinsystem was stimulated using the two kidney–one clip (2K-1C)model.31 Pharmacologic inhibitor studies of vascular homogenatesfrom 2K-1C animals demonstrated that the major source of O2–was a NAD(P)H oxidase that was activated by a protein kinaseC–dependent mechanism.31 Inhibition of ROS in models ofAngII infusion or 2K-1C partly attenuates hypertension, indicatingthat AngII-induced ROS is important for vasoconstriction inthese models.10
The mechanisms by which AngII activates NAD(P)H oxidase hasbeen the subject of active research. In vascular cells, caveolin1 (a component of caveolae/lipid rafts that are cholesterol-enrichedspecialized membrane microdomains) is necessary for AngII-mediatedRac1 and NAD(P)H oxidase activation and ROS generation.32 Principally,it has been found that AngII stimulates upregulation of variousNAD(P)H oxidase subunits, including Nox1, p47phox, p67phox,and p22phox, in various cell types.33–38 Functional evidencethat this induction of enzyme subunits is important comes fromexperiments interfering with the AngII-induced expression ofsubunits by antisense or small-inhibitory RNA technology.27,28,34In addition, some limited studies have confirmed these findingsin knockout mice. For example, AngII infusion leads to bluntedROS formation and an attenuated BP response in reduced Nox1-deficientmice.39 Similarly, mice deficient in the p47phox gene showeda reduced ROS formation and lower arterial BP during AngII infusion.36In contrast to AT1 receptor activation, it seems that AngII-mediatedstimulation of AT2 receptors downregulates several NAD(P)H oxidasecomponents (Nox1, p22phox, and p67phox).3 Conversely, AngIIfacilitates assembly of NAD(P)H oxidase subunits (Figure 2).AngII has been found to induce serine phosphorylation of p47phox,resulting in an increased binding of p47phox to p22phox.40 AngIIalso stimulates Rac1 by disrupting the binding of Rac to theGDP dissociation inhibitor RhoGDI. Rac1 in turn binds to andactivates Nox4, increasing ·O2– generation.41,42
Aldosterone can also induce ROS formation by increasing expressionof the p47phox and p67phox subunits of NAD(P)H oxidase.43,44In fact, some of the effects previously attributed to AngIIon NAD(P)H oxidase-mediated ·O2– formation maybe due to the secondary release of aldosterone. ROS formationin the heart induced by AngII infusion was prevented by themineralocorticoid receptor antagonist spironolactone and dependedon the presence of Nox2.45
Does AngII Stimulate ROS Formation by Systems Other than NAD(P)H Oxidase?
Recent evidence suggests that AngII stimulates mitochondrialROS generation through the opening of mitochondrial KATP channels,leading to redox-sensitive activation of mitogen-activated proteinkinases (MAPK).46 It is interesting that a process of AngII-mediatedpreconditioning has been described, at least in cardiac myocytes,in which NAD(P)H oxidase–derived ·O2– stimulatedKATP channels, facilitating the efflux of large mitochondrial-derivedamounts of ·O2– into the cytoplasm.47,48 The relationshipbetween generation of ·O2– in the mitochondrialrespiratory chain and NAD(P)H oxidase is complex, and it hasbeen shown that mitochondrial inhibitors suppress the inductionof Nox1.49
A more indirect effect of AngII on ROS formation may be mediatedthrough the hypoxia-inducible factor 1- (HIF-1). We previouslyshowed that AngII stimulates HIF-1 expression through AT2 receptorsvia suppression of prolyl hydroxylase 3, an enzyme that hydroxylatesHIF-1 with the consequence of inducing degradation of this factor.50,51In heterozygous mice partially deficient in HIF-1, ROS formationinduced by chronic intermittent hypoxia was, in contrast towild-type mice, absent, indicating a role of HIF-1 in the formationof ROS.52 However, a vice versa pathway has also been described,because ROS interact with and inhibit prolyl hydroxylase, leadingto a decrease in HIF-1 hydroxylation and stabilization of thistranscription factor.53
ROS are involved in many pathways, and potential molecular targetsare summarized in Figure 3. MAPK are activated by ROS. AngII-inducedp38 MAPK activation in vascular smooth muscle cells dependson H2O2.54 We found that AngII stimulates phosphorylation andactivation of extracellular signal–regulated kinase 1,2(ERK1,2) in renal tubular cells depending on NAD(P)H oxidase–mediated·O2– formation.55 AngII-mediated phosphorylationof the EGF receptor is sensitive to inhibition by antioxidants,presumably by interfering with the proteolytic cleavage of heparin-bindingEGF that transactivates the EGF receptor.56 Src tyrosine kinasesare also activated by AngII-stimulated ROS formation. Varioustyrosine phosphatases are susceptible to oxidation and inactivationby ROS because these enzymes contain a conserved cysteine thatis oxidized to sulfenic acid in the presence of ROS.57 In addition,transcription factors such as NF-B and AP-1 are induced by oxidativestress.58
Figure 3. Central role of AngII-stimulated ROS in several signal transduction pathways. ROS modify the activity of tyrosine kinases and phosphatases, activate MAPK, and stimulate transcription factors. Moreover, adhesion molecule expression is induced and matrix metalloproteinase activity is influenced. ROS can also directly change the activity of ion channels and alter the generation of NO by uncoupling of endothelial NOS (eNOS). All of these effects contribute to renal injury by inflammation and foster the development of renal fibrosis.
Matrix metalloproteinases 2 and 9, key enzymes in the degradationof extracellular matrix components, are activated by ROS.59Substantial experimental evidence indicates that AngII-inducedROS are potential regulators of adhesion molecule expression.Induction of intercellular adhesion molecule-1 and vascularcellular adhesion molecule-1 by AngII involves NAD(P)H oxidaseactivation.60 Together with NF-B–mediated transcriptionalactivation of chemokines, this induction of adhesion moleculescontributes to renal inflammation. ROS also activate ion channels(Ca2+ and K+) and modulate vascular tone through this mechanism.61
AngII-mediated ROS formation is important for renal growth processesthat are part of an adaptive process of surviving nephrons duringchronic renal injury.62 We intensively studied AngII-dependentgrowth of renal cells. AngII induces hypertrophy of culturedmouse proximal tubular cells, and this hypertrophy is associatedwith arrest of the G1 phase.63,64 This AngII-mediated cell-cyclearrest depends on induction of p27Kip1, an inhibitor of G1 phasecyclin-dependent kinase (CDK)/cyclin complexes.65–67 AngIIstimulates the accumulation of ·O2– in tubularcells by upregulation of p22phox.66 The ROS, in turn, activateERK1,2, and MAPK.55 Accordingly, we consequently asked whetherthe p44/42 MAPK may in turn directly phosphorylate p27Kip1.Activated ERK1,2 directly phosphorylates recombinant p27Kip1in vitro.68 Functional studies showed that serine178 mutation,in contrast to wild-type or serine,10 and threonine187 mutationsof p27Kip1 failed to promote hypertrophy, showing the role forspecific protein phosphorylation in mediating the effect ofAngII on cell hypertrophy.68 Although primarily derived fromcell culture studies, similar mechanisms are operative in vivo.69Infusion of AngII into naive rats (rate of 250 ng/min into maleWistar rats [body weight 200 g]) for 7 d increases formationof ·O2– in tubular cells and stimulates proteinexpression of p27Kip1.69 The infusion of AngII concomitantlyreduces tubular proliferation, indicating G1-phase arrest. Immunoprecipitationexperiments revealed that the increased p27Kip1 protein associateswith CDK 2.69 Co-administration of the radical scavenger dimethylthioureaeliminated this AngII-mediated p27Kip1 expression without reducingsystemic BP.69 Other work, mainly performed on endothelial andsmooth muscle cells, points to a role of AngII-induced ROS incell migration and apoptosis.70Table 1 shows various experimentalmodels of renal disease in which AngII-mediated ROS formationhas been implicated, mainly by administration of antioxidantsor inhibition of NAD(P)H oxidase activation.
Although numerous experimental studies have indicated a roleof AngII-mediated ROS formation, extending this concept to thepathophysiology and treatment of human renal disease has beenproblematic. Several descriptive studies on oxidative stressin various renal diseases exist. Women with preeclampsia havean agonistic antibody in the plasma that binds to AT1 receptorsthat activate NAD(P)H oxidase by inducing p22phox, p47phox,and p67phox.71 We and others have found in biopsies from patientswith different types of renal allograft rejection signs of oxidativestress associated with the apoptosis of renal cells.72,73 Ingeneral, human studies using vitamin E as an antioxidant havefailed to show any benefit, and some data from cardiovascularstudies even suggest that this treatment may be harmful.74–76Part of this problem may be that when vitamin E or other antioxidantsscavenge ·O2–, they become radicals themselvesthat have their own effects. N-acetylcysteine, a potential antioxidant,has been widely used in studies to prevent contrast media–inducedrenal injury.77–80 However, the current data are controversial,and it is unclear whether the effects are really due to scavengingof ROS or rather represent direct influence on renal creatininehandling.78,80,81 In hemodialysis patients, N-acetylcysteinereduces cardiovascular end points, but whether this intriguingeffect is due to the antioxidative effects of the substancerequires further studies.82 However, several studies showedthat angiotensin-converting enzyme inhibitor or AT1 receptorantagonist treatment reduces oxidative stress in patients withrenal diseases.83–85
Experimental studies provide ample evidence that AngII stimulatesintracellular formation of ·O2– by upregulatingsubunits of the membrane-bound NAD(P)H oxidase and by facilitatingassembly of subunits. Recent studies also suggest that mitochondrialROS generation is stimulated by AngII. ·O2– isinvolved in several signal pathways, and redox-sensitive transcriptionalfactors, including AP-1 and NF-B, suggest that ROS are an importantsecond messenger of AngII’s transcriptional effects. Theconcept of oxidative stress has changed insofar as early discretechanges occur within the cell or even an enzyme system withouta necessary modification of total cellular redox status. Thesesubtle changes may already influence the genetic program ofthe renal cells, leading to an altered transcriptosome. AngII-inducedROS may play a pivotal role in several pathophysiologic diseasesof the kidney and vasculature (e.g., glomerulonephritis, diabeticnephropathy, hypertension, acute renal failure, progressionof renal disease). Although inhibition of the RAAS in humansleads to a reduction in markers of oxidative stress, antioxidativeinterventions targeting on the level of total cellular redoxstatus (e.g., antioxidative vitamins) have been disappointing.Presumably, therapeutic approaches might better focus on repairingor inhibiting the function of individual enzymes [e.g., NAD(P)Hoxidase] involved in ROS generation. Interesting side effectsof drugs such as mycophenolate acid that have been shown toinhibit NAD(P)H oxidase may serve as paradigm for further developmentof antioxidative strategies to combat kidney diseases.86
This original work in the author’s laboratory is supportedby the Deutsche Forschungsgemeinschaft (Wo 460/2-8, Wo 460/12-2).Because of space restrictions, not all important studies inthis burgeoning field could be referenced, and we apologizeto all authors whose work was not quoted in this review.
Footnotes
Published online ahead of print. Publication date availableat www.jasn.org.
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