Renin-Angiotensin-Aldosterone System and Progression of Renal Disease
Christiane Rüster and
Gunter Wolf
Department of Internal Medicine III, Friedrich-Schiller-University, Jena, Germany
Address correspondence to: Dr. Gunter Wolf, Department of Internal Medicine III, University Hospital Jena, Erlanger Allee 101, D-07740 Jena, Germany. Phone: +49-03641-9324301; Fax: +49-03641-9324302; E-mail: gunter.wolf{at}med.uni-jena.de
Inhibition of the renin-angiotensin-aldosterone system (RAAS)is one of the most powerful maneuvers to slow progression ofrenal disease. Angiotensin II (AngII) has emerged in the pastdecade as a multifunctional cytokine that exhibits many nonhemodynamicproperties, such as acting as a growth factor and profibrogeniccytokine, and even having proinflammatory properties. Many ofthese deleterious functions are mediated by other factors, suchas TGF- and chemoattractants that are induced in the kidneyby AngII. Moreover, understanding of the RAAS has become muchmore complex in recent years with the identification of novelpeptides (e.g., AngIV) that could bind to specific receptors,elucidating deleterious effects, and non–angiotensin-convertingenzyme (ACE)–mediated generation of AngII. The abilityof renal cells to produce AngII in a concentration that is muchhigher than what is found in the systemic circulation and theobservation that aldosterone may be engaged directly in profibrogenicprocesses independent of hypertension have added to the complexityof the RAAS. Even renin has now been identified to have a "lifeon its own" and mediates profibrotic effects via binding tospecific receptors. Finally, drugs that are used to block theRAAS, such as ACE inhibitors or certain AngII type 1 receptorantagonists, may have properties on cells independent of AngII(ACE inhibitor–mediated outside-inside signaling and peroxisomeproliferator–activated receptor- stimulatory effects ofcertain sartanes). Although blockade of the RAAS with ACE inhibitors,AngII type 1 receptor antagonists, or the combination of bothshould be part of every strategy to slow progression of renaldisease, a better understanding of the novel aspects of theRAAS should contribute to the development of innovative strategiesnot only to completely halt progression but also to induce regressionof human renal disease.
One of the major challenges in today’s nephrology is theincreasing number of patients with ESRD. Moreover, it has beenappreciated more recently that patients with already relativelyminor impairment of renal functions have an increased risk forcardiovascular diseases, long before ESRD is reached. Therefore,a better understanding of the pathophysiology of chronic renaldisease is mandatory to develop strategies to prevent the progressionof renal disease or even to restore renal function by inducingregression (1). Regardless of the primary entity, progressionof renal disease is characterized by pathomorphologic changesthat comprise early renal inflammation, followed by subsequenttubulointerstitial fibrosis, tubular atrophy, and glomerulosclerosis(1). The renin-angiotensin-aldosterone system (RAAS) plays apivotal role in many of the pathophysiologic changes that leadto progression of renal disease. This article highlights someof the more recent molecular insights into the complexity ofthe RAAS and its role in chronic renal disease. Because of spacerestriction, the many clinical studies that deal with the RAASare not covered, and the reader is referred to excellent reviews(2,3).
Traditionally, the RAAS was considered as an endocrine systemwith angiotensinogen, produced in the liver, that is cleavedby renin released from renal juxtaglomerular cells (4). By thisway, angiotensin I (AngI) is generated, which, in turn, is furthercleaved by angiotensin-converting enzyme (ACE) activity of thelungs into the active form of AngII. AngII then binds to specificreceptors in adrenal cortex, resulting in release of aldosterone.In this classical view, the cardinal function of the RAAS ismaintaining of BP by AngII-induced vasoconstriction and aldosterone-mediatedsodium retention in the collecting duct (4). However, the RAAShas become complex in recent years, and novel components ofthis network have been identified. Figure 1 provides an overviewof our current understanding.
Figure 1. Overview of the renin-angiotensin-aldosterone system (RAAS). The system has become increasingly complex with alternative ways of angiotensin II (AngII) formation besides angiotensin-converting enzyme (ACE; (Chymase, chymostatin-sensitive AngII-generating enzyme [CAGE]), a second form of ACE (ACE2), and novel peptides such as AngIV, angiotensin 1-9, and angiotensin 1-7. Clinically important could be that AngII can bind to AngII type 2 (AT2) receptors and AngIV to AT4 receptors that are not antagonized by sartanes, inducing proinflammatory and profibrotic effects (e.g., induction of chemokines, stimulation of plasminogen activator inhibitor-1).
The most widely known enzyme that is capable of AngII formationis ACE, but it is not the only one. Other AngII-generating enzymesinclude the serine protease chymase, which is supposed to mediate>80% of AngII formation in the heart and >60% in the vessels(5). ACE inhibitors do not reduce chymase activity. Upregulationof chymase, mainly in the tubules, is observed in renal biopsiesof patients with diabetic nephropathy (5). These findings indicatethat under pathologic conditions, an upregulation of chymaseoccurs and increased local AngII generation cannot be attenuatedby ACE inhibitors. Mechanical stress of podocytes stimulateslocal AngII synthesis by non-ACE pathways that presumably involvechymase (6), yet the exact role of chymase-mediated AngII formationfor renal disease in humans is unclear, and ACE inhibitors clearlyslow progression of disease.
A novel enzyme similar to ACE, called angiotensin-convertingenzyme 2 (ACE2), has been identified (7). ACE2 is expressedpredominantly in vascular endothelial cells, including thoseof the kidney (8). In contrast to the "classic" ACE, which convertsAngI to the octapeptide AngII, ACE2 cleaves one amino acid lessfrom AngI so that in a first step, angiotensin 1-9 is formed(7). Angiotensin 1-9 is thought to potentate AngII-mediatedvasoconstriction on isolated rat aortic rings and to have vasodepressoreffects in conscious rats. It also was found that angiotensin1-9 augments bradykinin action on its B2 receptor probably byinducing conformational changes (9). In a second step, angiotensin1-9 can be converted to angiotensin 1-7 by the "classic" ACE.A major pathway of angiotensin 1-7 degradation’s convertingthe peptide into inactive fragments is mediated by ACE itself.Angiotensin 1-7 is known to act as a vasodepressor agent andis involved in apoptosis and growth arrest. The protein productof the c-mas gene is a receptor for angiotensin 1-7. Furtherexperimental studies show anti-inflammatory and antifibroticeffects of angiotensin 1-7. The local expression of ACE2 correlatesclosely with the concentration of angiotensin 1-7 and leadsto an, at least partial, antagonism of AngII. Thus, ACE inhibitioncan lead to increased angiotensin 1-7 levels while reducingAngII in parallel (9). However, one should be aware that themajority of data for angiotensin 1-7 stems from the cardiovascularsystem, and the relevance for renal disease is unclear.
AngII is metabolized by peptidases, such as aminopeptidase A,into AngIII and further into AngIV (10). AngIII interacts withAngII type 1 (AT1) and AT2 receptors, albeit with a lower affinity,and exhibits principally similar effects as AngII. AngIV bindsto a specific receptor called AT4, which is widely expressedin the kidney, including endothelial cells and proximal as wellas convoluted tubules. The AT4 receptor, by protein purificationand peptide sequencing, has been identified to be insulin-regulatedaminopeptidase (11).
The multiple effects of AngII are mediated by different receptors.The two major AngII receptors, AT1 and AT2, are differentiallyexpressed within in the kidney (12). Both are characterizedby the configuration of a seven-transmembrane receptor but shareonly approximately 30% homology on the protein level. AT1 receptorsare coupled to heterotrimeric G proteins and mediate different,mainly second-messenger signal transduction pathways, such asactivation of phospholipases, inhibition of adenylate cyclase,stimulation of tyrosine phosphorylation, extracellular signal–regulatedkinases 1 and 2, the phosphatidylinositol 3-kinase–dependentkinase Akt, and the mammalian target of rapamycin/S6 kinasepathway (12). AT1 receptor activation also stimulates releaseof reactive oxygen species by a mechanism that involves activationof the membrane-bound NAD(P)H oxidase.
Lautrette et al. (13) recently described a novel mechanismsby which AngII transactivates the EGF receptor during renalinjury in a model of chronic AngII infusion over 2 mo. Theyfound that AngII induced secretion of TGF- that binds to andactivates the EGF receptor, explaining how AngII through transactivationof the EGF receptor could exhibit tyrosine kinase activity (13).
AT2 receptors are involved in an increase in intracellular proteinphosphatase activity (14). The number of AT1 and AT2 receptorsis developmentally regulated, and during maturation of the kidney,AT1 receptor expression becomes more abundant.
AT1 receptor expression is upregulated by various stimuli, suchas hypercholesteremia or a change in osmolarity, but is suppressedby high AngII concentrations or glitazones (12). N-acetylcysteine,an antioxidant that reduces disulfide bonds, decreased AngIIbinding to AT1 receptors (15). AT2 receptors are not suppressedby AngII, but, interesting, they are upregulated in injuredtissue and during inflammation (14). In particular, AT2 receptorsare re-expressed in the kidney during renal injury and remodelingnephrons. The ability of AT1 receptors to form homodimers aswell as heterodimers with other receptors such as the bradykininreceptor results in a significant acceleration of signal transductionactivity after AngII stimulation (16).
Almost all AngII-induced physiologic and pathophysiologic functions,such as vasoconstriction, aldosterone release, stimulation oftubular transport, proinflammatory effects, and profibrogenicand growth stimulatory actions, are mediated by AT1 receptors(12). The role of AT2 receptors seems less clear. Activationof AT2 receptors leads to a decrease in BP through release ofnitric oxide, inhibits growth and induces differentiation, andalso is involved in mediation of apoptosis (14). Recent evidencesuggests that activation of NF-B, an important proinflammatorytranscription factor, is mediated by AT1 and AT2 receptors.The question of which pathophysiologic effects are mediatedthrough the AT2 receptor is of clinical relevance because notall important pathophysiologic functions of AngII may be antagonizedby AT1 receptor blockers.
Agonistic antibodies against AT1 receptors have been identifiedin pregnant women with preeclampsia and in patients with secondarymalignant hypertension (17). These autoantibodies against AT1receptors lead to a stimulation of the receptor (18). Some renaltransplant patients who have chronic allograft failure withoutclassic HLA antibodies have such agonistic antibodies againstthe AT1 receptor, and they were involved in vasculitis withdestruction of the renal allograft (18).
Polymorphisms for different components of the RAAS, such asACE, angiotensinogen, or AT1 receptors, have been describedwith controversial results (19), mainly explained by the differentethnic backgrounds of the study populations. Huang et al. (20)induced diabetes in mice that had one, two, or three copiesof the ACE gene. Twelve weeks later, the three-copy diabeticmice had increased BP and overt proteinuria. Proteinuria wascorrelated to plasma ACE level in the three-copy diabetic mice.Thus, a modest genetic increase in ACE levels leads to aggravationof diabetic nephropathy in mice in comparison with reduced ACEgene expression (20). These data indicate that there likelyis some genetic influence on the activity of the RAAS, but howthis translates into the individual risk for predispositionor progression of renal disease remains unclear.
During the past two decades, local RAAS have been describedto operate independent from their systemic counterpart (21).A local RAAS including all its components could have been shownin the proximal tubular cells of the kidney (Figure 2). Proximaltubular cells actively produce AngII and also secrete angiotensinogeninto the urine (21). Intraluminal angiotensinogen may be convertedin the distal tubules to AngII, and recent observations suggestthat it leads to induction of sodium channels independent ofaldosterone (22). Hyperglycemia and proteinuria could stimulatelocal AngII synthesis, mainly by oxygen species as signal transducers(12). Renal injury activates the local RAAS directly and indirectly.For example, a reduction in calcitriol stimulates renin transcriptionaccompanied by local increase of AngII, demonstrating an indirectactivation (12).
Figure 2. Proximal tubular cells as an example of a local RAAS. Tubular cells could generate AngII in nanomolar concentrations and secrete into the tubular fluid as well as the interstitial space. Furthermore, tubular cells secrete intact angiotensinogen into the tubular fluid. Cells also could take renin and angiotensinogen up from the circulation, indicating a close interaction with the systemic RAAS. Although proximal tubular cells have ACE in their brush border membranes, it is controversial whether intracellular ACE contributes to AngII formation.
Of clinical relevance is the observation that complete systemicinhibition of the AngII formation by an ACE inhibitor is notaccompanied by a significantly reduced intrarenal AngII production(23). Intrarenal AngII is found regionally compartmentalized(24). Intact AngII is found in endosomes that are derived fromreceptor-mediated endocytosis. This might be an important mechanism,because observations in certain cells demonstrated that AngIIcan be translocated into the nucleus, where it directly regulatesthe gene transcription (12). AngII has many diverse effectson renal cells, some of which are depicted in Figure 3.
Besides hypertension, proteinuria is one of the most importantrisk factors for the progression of renal diseases. As outlinedin detail in the accompanying article by Remuzzi et al., increasedtubular absorption of filtered proteins induces tubulointerstitialinflammation, ultimately resulting in tubular atrophy, interstitialfibrosis, and loss of renal function. The RAAS plays an importantrole in many of the pathophysiologic processes that are associatedwith proteinuria. First, AngII is a mediator of proteinuria.It preferentially raises efferent glomerular arteriole resistance.AngII induces TGF-1 in the various renal cells (25). Sharmaet al. (26) recently showed that TGF-1 impairs the autoregulationby afferent arterioles. Because afferent arterioles respondto an increase in arterial pressure with vasoconstriction, impairedautoregulation in the presence of TGF-1 leads to an elevationin transcapillary pressure, particularly during systemic hypertension.Thus, AngII directly (efferent vasoconstriction) and indirectly(TGF-1–mediated impaired afferent arteriole autoregulation)enhances capillary filtration pressure.
Moreover, AngII exhibits direct effects on the integrity ofthe ultrafiltration barrier. It has been shown that AngII decreasesthe synthesis of negatively charged proteoglycans and additionallysuppresses nephrin transcription (12,27). Because intact nephrin–nephrinsignaling is important for the survival of podocytes, AngII-mediatedsuppression of nephrin results in podocyte apoptosis. Vascularendothelial growth factor (VEGF) also could be important inincreasing the permeability of the ultrafiltration barrier.Neutralization of VEGF with an antibody reduces proteinuriaby one half in a model of diabetic nephropathy (28). AngII stimulatesVEGF expression through AT1 and AT2 receptor. The increase ofVEGF expression through AT2 receptors presumably is mediatedby an increase in hypoxia-inducible factor 1 because AT2 receptoractivation led to a downregulation of prolyl hydroxylase 3,an enzyme that is important for initiating the degradation ofhypoxia-inducible factor 1 (29). AngII-induced synthesis ofthe 3 chain of collagen type IV, the principal ingredient ofthe glomerular basement membrane, is mediated by VEGF and TGF-1(30). Consequently, AngII through hemodynamic and nonhemodynamicmechanisms increases proteinuria.
In the proximal tubule, albumin and other ultrafiltered proteinsare reabsorbed by endocytosis involving megalin and cubulin(31). AngII stimulates albumin endocytosis in proximal tubulecells via AT2 receptor–mediated protein kinase B activation.However, an increase in tubular albumin reabsorption activatesthe tubular RAAS, leading to a vicious circle (32). Albuminuptake induces a deluge of proinflammatory and profibrogeniccytokines such as RANTES, monocyte chemoattractant protein-1,IL-8, endothelin, and TGF-1 (33). This stimulates the migrationof immune-competent cells into the interstitium.
AngII activates through AT1 and AT2 the proinflammatory transcriptionfactor NF-B (34). In addition, AngIII and AngIV can stimulateNF-B (33). It therefore is obvious that sartanes could blockonly some proinflammatory effects of the RAAS. The Rho kinasepathway is involved in AngII-mediated NF-B activation. Furthermore,AngII stimulates the transcription factor Ets, and this factoris a critical regulator of vascular inflammation with T celland macrophages/monocytes recruitment to the vessel wall (35).We recently demonstrated another mechanism for how AngII couldcontribute to renal inflammation. AngII upregulates on mesangialcells Toll-like 4 receptors that bind LPS (36). This AngII-mediatedToll-like 4 receptor upregulation resulted in enhanced NF-Bactivation (36). The recruitment of inflammatory cells intothe glomerulus as well as into the tubulointerstitium playsan pivotal role in progression of chronic renal disease. AngIIstimulates upregulation of adhesion molecules such as vascularcellular adhesion molecule-1, intracellular adhesion molecule-1,and integrins, allowing circulating immune cells to adhere oncapillaries. NF-B–mediated transcription of chemokines,including monocyte chemoattractant protein-1, RANTES, and otherchemokines, then is responsible for renal tissue infiltrationwith leukocytes. In addition, AngII may directly stimulate proliferationof lymphocytes (33). It is interesting that lymphocytes arean active source of AngII, further amplifying proinflammatoryeffects (37). It is obvious that the AngII-mediated proinflammatoryeffects amplify the pathophysiologic changes that are inducedby proteinuria.
AngII stimulates proliferation of mesangial cells, glomerularendothelial cells, and fibroblasts. In contrast, the peptideinduces hypertrophy of proximal tubular cells by a p27Kip1-mediatedcell-cycle arrest (38,39). Proliferation of glomerular cellsand fibroblasts could enhance structural renal damage and fibrosis.AngII-induced tubular hypertrophy, although initially an adaptiveresponse to loss of functional nephrons, is over the long termmaladaptive and likely fosters development of tubular atrophyand interstitial fibrosis. Moreover, AngII induces apoptosisunder certain conditions in vivo and in vitro (39). Experimentalevidence suggests that AT1 and AT2 receptors are involved inthis effect. The decision of whether cells undergo growth stimulatoryeffects (proliferation, hypertrophy) or rather apoptosis maydepend on the presence of additional growth factors and cytokinesand the activation state of the cell. Furthermore, the AngIIconcentration may play a role, but why the peptide mediatesgrowth stimulatory effects under certain experimental conditionsand induces apoptosis in other settings is not completely understood.
Probably the most direct evidence that AngII is involved inrenal scarring stems from targeted overexpression of renin andangiotensinogen in rat glomeruli (25). Seven days after transfection,extracellular matrix (ECM) was expanded in rats with glomerularrenin and angiotensinogen overexpression without systemic hypertension.AngII induces mRNA encoding the ECM proteins type I procollagenand fibronectin in cultured mesangial cells and also stimulatesthe transcription and synthesis of collagen type 1(IV) and 3(IV)but not type I in cultured proximal tubular cells (25). Thestimulatory effects of AngII on collagen expression dependson TGF-1 expression. AngII stimulates proliferation of culturedrenal fibroblasts and increases mRNA expression of TGF-, fibronectin,and type I collagen. A novel twist to the whole story is therecent observation that renin alone, through a specific receptor,stimulates TGF-1 in mesangial cells (40). These findings raisethe intriguing possibility that elevated renin, as a consequenceof ACE inhibitor or AT1 receptor treatment, may contribute directlyto renal fibrosis via TGF-1 despite AngII blockade. AngII increasesconnective tissue growth factor (CTGF) in the kidney (41). CTGFis a novel fibrotic mediator and is stimulated by TGF-. However,AngII-induced CTGF expression also occurs independent of TGF-(41).
A delicate balance between ECM synthesis and degradation underphysiologic conditions prevents fibrosis. AngII induces viaAT1 receptors plasminogen activator inhibitor-1 (PAI-1) andtissue inhibitor of matrix metalloproteinases-1 (TIMP-1). PAI-1and TIMP-1 inhibit metalloproteinases and thereby matrix turnover,resulting in accumulation of ECM. Through stimulating the expressionof PAI-1 in the proximal tubules via the AT4 receptor, AngIVcan play a role in the development of renal fibrosis independentfrom the activation of AT1 and AT2 receptors (42). Because ofupregulation of AngIV, which generates enzymes under conditionswith high local AngII concentrations and in diabetic nephropathy(10), accelerated degradation of AngII into AngIV could activateAT4 receptors, inducing PAI-1.
Ingenious experiments have demonstrated that more than one thirdof local fibroblasts in renal interstitial fibrosis originatefrom tubular epithelial cells through a process called epithelial-to-mesenchymaltransition (EMT). The molecular mechanism of EMT was reviewedpreviously in detail (43). EMT may be important in later stagesof renal disease progression, leading to interstitial fibrosisand tubular atrophy because of vanishing epithelial cells. Oneimportant mediator of EMT is TGF-1, and AngII could contributeto EMT through induction of this profibrotic factor (43). EMTis antagonized by hepatocyte growth factor. Because AngII suppresseshepatocyte growth factor synthesis, AngII additionally may fosterEMT via a reduction of its antagonist (44).
ACE Inhibitor and AT1 Receptor Effects Independent of the RAAS
Recent evidence suggests that ACE inhibitors as well as AT1receptor blockers can influence cellular functions independentof inhibition of the RAAS. For example, ACE inhibitors blockthe hydrolysis of N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP).Some protective effects of ACE inhibitor (e.g., inhibition offibrosis, reduction of inflammatory cell infiltration) are theresult of the inhibition of Ac-SDKP hydrolysis rather than inhibitionof AngII formation in a model of AngII-induced cardiac fibrosis(45). Whether similar mechanisms are operative in the kidneyremains unclear.
Using endothelial cells, it has been demonstrated that the ACEinhibitors ramiprilat and perindoprilat increase CK2-mediatedphosphorylation of serine1270 (46). Furthermore, ACE inhibitortreatment increased the activity of N-terminal kinase in endothelialcells. These provocative findings indicate that ACE inhibitorsmay mediate cellular function by "outside-in" signaling directlythrough ACE, an effect that is totally independent of the generationof AngII (46).
Evidence is accumulating that some AT1 receptor antagonists,such as telmisartan, activate the peroxisome proliferator–activatedreceptor- (PPAR-), a widely known target for treatment of themetabolic syndrome and diabetes (47). Recent studies have indicatedthat in addition to antidiabetic properties, PPAR- activatorsmay improve renal disease, normalize hyperfiltration, and reduceproteinuria (47). The PPAR-–activating properties of certainsartanes do not require the presence of AT1 receptors and arecaused by the molecular structure of the specific sartanes (47).Therefore, it is possible that some of the protective effectsof AT1 receptor blockers in slowing the progression of chronicrenal disease are due to actions that are independent of theRAAS action.
The classic understanding of aldosterone as a hormone that isproduced in the adrenal cortex, which is involved in the reabsorptionof sodium and the secretion of potassium and protons in thecollecting duct, needs to be extended. These aldosterone effectshave been explained as genomic effects that are caused by increasedtranscription of different target genes after binding of aldosteroneto cytoplasmic receptors. Newer data provide evidence that nongenomiceffects of aldosterone, such as the activation of certain signaltransduction pathways, occur in several organs, including thekidney (48). Aldosterone also is generated in many other tissuesbesides the adrenal cortex. In various animal models of renaldiseases, aldosterone is involved in endothelial dysfunction,inflammation, proteinuria, and fibrosis (48). Aldosterone increasesthe effect of AngII, induces the generation of reactive oxygenspecies, and leads to an acceleration of the AngII-induced activationof mitogen-activated protein kinases (49). These findings indicatethat blockade of mineralocorticoid receptors presumably is beneficialeven in situations with high AngII, because common signal transductionpathways between the two systems are interrupted. The firstclinical studies seem to be showing that blockade of the aldosteronereceptors provides additional renal protection even in the presenceof ACE inhibition or AT1 receptor antagonism. However, the potentialthreat of hyperkalemia with such an approach requires furtherclinical studies to test the safety of this treatment.
The RAAS has come a long way since we described more than 15yr ago structural and profibrotic effects of AngII on renalcells (38). This fascinating system has become increasinglycomplex, and the search for new members still continues. AngIIhas emerged from a vasoconstrictor to the major multifactorialpeptide involved in the progression of renal disease. A comprehensiveunderstanding of the RAAS with novel pharmacologic approachesto interfere with its members (e.g., the renin inhibitor askiren)hopefully will provide tools to halt progression completelyand induce regression of renal disease.
Acknowledgments
Original studies in the authors' laboratory are supported bythe Deutsche Forschungsgemeinschaft.
We apologize to all of the contributors in this burgeoning fieldwhose publications could not be acknowledged because of restrictionson the number of references.
G.W. thanks Eric G. Neilson for support, encouragement, andunbelievable foresight in the late 1980s, when nobody believedthat AngII is more than a vasoconstrictor.
Footnotes
Published online ahead of print. Publication date availableat www.jasn.org.
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and chemoattractants that are induced in the kidney by AngII. Moreover, understanding of the RAAS has become much more complex in recent years with the identification of novel peptides (e.g., AngIV) that could bind to specific receptors, elucidating deleterious effects, and non–angiotensin-converting enzyme (ACE)–mediated generation of AngII. The ability of renal cells to produce AngII in a concentration that is much higher than what is found in the systemic circulation and the observation that aldosterone may be engaged directly in profibrogenic processes independent of hypertension have added to the complexity of the RAAS. Even renin has now been identified to have a "life on its own" and mediates profibrotic effects via binding to specific receptors. Finally, drugs that are used to block the RAAS, such as ACE inhibitors or certain AngII type 1 receptor antagonists, may have properties on cells independent of AngII (ACE inhibitor–mediated outside-inside signaling and peroxisome proliferator–activated receptor-
stimulatory effects of certain sartanes). Although blockade of the RAAS with ACE inhibitors, AngII type 1 receptor antagonists, or the combination of both should be part of every strategy to slow progression of renal disease, a better understanding of the novel aspects of the RAAS should contribute to the development of innovative strategies not only to completely halt progression but also to induce regression of human renal disease. 
that binds to and activates the EGF receptor, explaining how AngII through transactivation of the EGF receptor could exhibit tyrosine kinase activity (13). 
B, an important proinflammatory transcription factor, is mediated by AT1 and AT2 receptors. The question of which pathophysiologic effects are mediated through the AT2 receptor is of clinical relevance because not all important pathophysiologic functions of AngII may be antagonized by AT1 receptor blockers. 
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Abstract
Introduction
