ACE inhibitors and AT1 receptor antagonists—beyond the haemodynamic effect

Marta Ruiz-Ortega, Oscar Lorenzo, Monica Ruperez and Jesus Egido

Renal Unit, Fundación Jiménez Díaz, Universidad Autónoma, Madrid, Spain

Introduction

The classical view of angiotensin II (Ang II) as a vasoactive agent that participates in local and systemic haemodynamic regulation has been recently enlarged to consider it as a true cytokine with an active role in renal and cardiovascular pathology (reviewed in [1,2]). In several models of kidney damage, the blockade of Ang II actions by angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor antagonists ameliorates proteinuria, inflammatory cell infiltration and fibrosis [3–6]. In addition, several authors, including ourselves, have demonstrated that Ang II is a renal growth factor that modulates cell growth and extracellular matrix production [1,2,,7,,8]. Moreover, Ang II participates in the inflammatory response in the kidney through the synthesis of chemotactic factors [9]. Finally, recent studies suggested that angiotensin peptides other than Ang II are bioactive agents with potential implication in renal pathology (reviewed in [10]). In this editorial, we comment on some new aspects of the renin–angiotensin system (RAS) that provide a wider view of this complex system.

Action of Ang II on cell growth and matrix synthesis

One common feature of progressive renal diseases is the proliferation of resident renal cells and accumulation of extracellular matrix [11]. Several studies have demonstrated that local Ang II could contribute to these phenomena [1–8]. Ang II modulates cell growth, inducing hyperplasia/hypertrophy, depending on the cell type [1]. Ang II activates mesangial cells, tubular cells, and renal interstitial fibroblasts, increasing the expression and synthesis of extracellular matrix proteins [1,2,8]. Some of these effects seem to be mediated by the release of growth factors such as transforming growth factor-ß (TGF-ß) and platelet-derived growth factor (PDGF) [1,2,12]. In experimental models of renal damage elevated renal Ang II production as well as upregulation of renal TGF-ß expression was noted, and this was associated with increased expression of mRNA of extracellular matrix proteins and matrix deposition. These abnormalities were reduced by ACE inhibition and AT1 receptor blockade [5,6,12].

Ang II and mononuclear cell recruitment

A novel function of Ang II is its participation in inflammatory cell recruitment. The first evidence of a potential role of Ang II in immune responses was suggested by the presence of Ang II receptors on human monocytes [13], as well as by the accumulation of mononuclear cells in the kidney of rats after 7–14 days of systemic Ang II infusion [14–16]. Ang II may be involved in different steps in the onset and progression of inflammation. This peptide is a chemotactic factor for mononuclear cells, which induces adhesion molecules expression in human endothelial cells and activates human monocytes, leading to increased adhesion to endothelial cells [17–20].

Most kidney diseases are characterized by the infiltration of monocytes, and those cells seem to play a crucial role in the progression to irreversible structural renal changes [21]. Many studies have shown that in several models of renal injury, associated or not to hypertension, ACE inhibitors reduce the number of infiltrating cells in the glomeruli and interstitium [5,22,23]. We have recently demonstrated that this beneficial effect could be due to interference with chemokine production [9]. Among chemokines, monocyte chemoattractant protein-1 (MCP-1) has emerged as an important mediator of monocyte infiltration [24,25]. Increased renal MCP-1 expression has been reported in experimental and human nephritis [26]. Moreover, the administration of anti-MCP-1 antibodies to rats with nephrotoxic nephritis and with anti-thymocyte antibody-induced nephritis reduced the glomerular infiltration by monocytes/macrophages [27,28]. Recent studies have further expanded the potential link between Ang II and MCP-1. Thus, in a model of immune complex nephritis, characterized by increased local Ang II generation in the absence of systemic hypertension, we have observed an upregulation of renal MCP-1 (mRNA and protein), coincidentally with mononuclear cell infiltration. Both effects were markedly reduced by treatment with the ACE inhibitor quinapril [9]. MCP-1 upregulation was seen in glomerular and tubular epithelial cells, as well as in infiltrating mononuclear cells, suggesting that this chemokine is produced by both intrinsic and infiltrating cells in paracrine/autocrine fashion as hypothesized by Tang et al. [27]. In cultured glomerular mesangial cells and mononuclear cells, Ang II is a potent activator of MCP-1, to an extent comparable to that of other cytokines [9]. The role of Ang II in immune-mediated nephritis and in the regulation of MCP-1 expression has been recently confirmed in a model of antiglomerular basement membrane nephritis induced in AT-1a-deficient homozygous mice [29]. All these data strongly suggest that Ang II plays a central role in the regulation of inflammatory cell recruitment during renal injury via chemokine production.

Angiotensin receptors and inflammation

Ang II elicits cellular responses through its binding to two specific receptor subtypes, AT1 and AT2 [30]. Most of the known actions of Ang II are mediated by AT1, such as vasoconstriction and deposition of matrix [1,2]. The receptor subtype involved in promoting inflammatory processes in the kidney is not yet elucidated; however, in the model of unilateral ureteral obstruction, monocyte/macrophage infiltration was only reduced by ACE inhibition, but not by AT1 receptor blockade [23]. In the models of mesangial proliferative nephritis and ureteral obstruction treatment with AT1 receptor antagonists caused a significant reduction, but not complete abolition, of renal MCP-1 expression [31,32]. A similar reduction of MCP-1 was observed in AT1 knockout mice [29]. On the other hand, in cultured glomerular endothelial cells, Ang II induced the expression of another chemokine, RANTES, through the AT2 receptor [16]. Moreover in vivo treatment with an AT2 antagonist diminished Ang II-induced glomerular monocyte infiltration [16]. The effect of AT2 inhibition on MCP-1 expression is at present unknown. Although future studies are necessary to clarify this point, these data suggest that ACE inhibitors or a combination of AT1 and AT2 blockers could be more effective than an AT1 receptor antagonist alone in the control of inflammatory cell infiltration. Finally, an effect of Ang II on MCP-1 production is not only demonstrable in renal cells: Ang II also increases MCP-1 expression in vascular smooth muscle [33], as well as in various target organs of hypertensive rats [35]. On the whole, such experimental evidence shows that Ang II must be viewed as a true cytokine that is involved in the regulation of inflammatory responses.

Ang II and nuclear factor-{kappa}B

The molecular signalling pathways elicited by Ang II have been investigated extensively. Ang II activates several second-messenger systems, including calcium mobilization and activation of protein kinases, such as the protein kinase C and mitogen activated proteins (MAP) cascades [30,35]. One important event in the cellular response to stimulation is the transduction of the signals to the nucleus. Some studies have shown that Ang II activates some nuclear transcription factors, including STAT family, AP-1 and CREB [35–38]. These proteins can translocate into the nucleus where they bind to specific DNA sequences, increasing the transcription of related genes. We have demonstrated that Ang II activates nuclear factor-{kappa}B (NF-{kappa}B) in vascular smooth muscle and mesangial cells [9,33]. NF-{kappa}B plays an important role in the regulation of the expression of proinflammatory genes, cell adhesion proteins, nitric oxide synthase and angiotensinogen, and other gene products involved in inflammation, immune response, renal damage, and cell proliferation [39,40]. In a normotensive model of immune glomerulonephritis, we found elevated tissue NF-{kappa}B activity that was well correlated with mononuclear cell infiltration, and renal MCP-1 expression that was diminished by ACE inhibition [9]. Moreover, in the model of ureteral obstruction which is characterized by an increase in the expression of MCP-1 and adhesion molecules (ICAM-1 and VCAM-1), two different studies have shown that NF-{kappa}B activity was elevated in the kidney cortex [41,42]. We have recently observed that after systemic infusion of Ang II renal NF-{kappa}B activity increases both in resident renal cells and in infiltrating monocytes [43]. Moreover, in other pathological settings associated with local Ang II production, such as experimental models of atherosclerosis and the model of wounded aortic endothelium, elevated tissue NF-{kappa}B activity was correlated with expression of MCP-1 and leukocyte adhesion molecule VCAM-1 respectively [33,44]. All these data strongly suggest that NF-{kappa}B is involved in the pathogenesis of renal and cardiovascular disease. In addition, the anti-inflammatory effect of ACE inhibitors may be due to the decreased activation of NF-{kappa}B.

Such new data suggest a novel mechanism of how Ang II affects the inflammatory process, i.e. through NF-{kappa}B activation (see Figure 1Go]. In mesangial cells, Ang II caused a rapid and dose-related activation of NF-{kappa}B, with a potency similar to that of inflammatory cytokines such as TNF-{alpha}>, as indicated by mobility shift assays [9]. Several Ang II-induced genes are regulated by NF-{kappa}B, including chemokines (MCP-1 and RANTES), cytokines (IL-6) and angiotensinogen [9,16,45,46]. We have observed that Ang II-induced NF-{kappa}B activation preceded upregulation of MCP-1 gene expression [9]. The rapid rise of MCP-1 mRNA levels induced by Ang II, the kinetics of NF-{kappa}B activation, and the effect of NF-{kappa}B inhibitors on Ang II-induced MCP-1 expression, are consistent with a role for NF-{kappa}B in transcriptional activation of MCP-1 gene, as shown for inflammatory cytokines as IL-1ß> [47]. Another point under investigation is the receptor subtype involved in this process. Ang II increased the synthesis of IL-6 and angiotensinogen through the AT1 receptor [45,46] and expression of RANTES through the AT2 receptor [16]. In vascular smooth muscle cells, using specific Ang receptor antagonists, we have observed that the effect of Ang II on NF-{kappa}B activation and I{kappa}B{alpha} degradation was mediated by AT1 and AT2 receptors (unpublished data). Moreover, in vivo Ang II infusion increased renal NF-{kappa}B activity, and this was diminished at least in part, by treatment with AT1 and AT2 receptor antagonists [43]. In rats with unilateral ureteral obstruction both AT1 and AT2 antagonists decreased NF-{kappa}>B activation in the obstructed kidney [48]. Thus, this transcription factor apparently regulates some effects which are ascribed to the AT2 receptor, such as cell differentiation, apoptosis, and mononuclear cell recruitment [49,50,16], as well as other processes mediated by the AT1 receptor, such as cell proliferation and expression of cytokine and angiontesinogen mRNA [1,2,45,46]. NF-{kappa}B also regulates other proteins, including TNF-{alpha}, IL-1ß>, inducible nitric oxide synthase, and cycloxygenase-2. These proteins could potentially also be modulated by Ang II in renal cells. The above data document the complex mechanisms through only Ang II-induced tissue injury. They also illustrate that the field to be investigated is wide.



View larger version (38K):
[in this window]
[in a new window]
 
Fig. 1. Ang II could modulate inflammatory cell infiltration in the kidney through NF-{kappa}B activation.

 

New aspects of the RAS. The Ang II degradation products

Although Ang II has been considered the effector peptide of the renin–angiotensin system, other angiotensin peptides also posses biological activities (review in [10]). Ang III presents some physiological functions similar to Ang II in the cardiovascular and central nervous systems [10]. Some effects of Ang (1–7) are opposite to those of Ang II. Ang (1–7) acts as a vasodilator and inhibits growth of vascular smooth-muscle cells [10]. Some of the actions of Ang II apparently are in reality due to these degradation peptides. Thus, the release of vasopressin requires the conversion of Ang II to Ang III [51], and the expression of the plasminogen activator inhibitor-1 induced by Ang II is mediated by Ang IV through the AT4 receptor [52]. The role of these Ang degradation products in the genesis of renal injury is under investigation. Renal infusion of Ang III into rats causes proteinuria [53]. In renal interstitial fibroblasts and mesangial cells, Ang III induced c-fos gene expression, increased TGF-ß> mRNA expression, and fibronectin production [54], suggesting that this peptide could participate in the control of cell proliferation and matrix accumulation observed during renal damage. In addition, we have observed that Ang III also upregulated MCP-1 gene expression, as occurs with Ang II (unpublished data). These data support the hypothesis that Ang II is not the one and only effector peptide of the RAS. As more and more information accumulates, we are forced to modify our classical view of this system.

Acknowledgments

The papers cited in this review have been supported by grants from Ministerio de Educación y Ciencia (PM 94/211, PM 95/93, PM97/85, SAF 97/55), EU Concerted Action Grant, BMH4-CT98-3631 (DG12-SSMI) and Instituto de Investigaciones Nefrológicas ‘Reina Sofia’.

Notes

Correspondence and offprint requests to: Jesus Egido MD, Renal and Vascular Research Laboratory, Fundación Jiménez Diaz, Avda. Reyes Católicos, 2, E-28040 Madrid, Spain. Back

References

  1. Egido J. Vasoactive hormones and renal sclerosis (Nephrology Forum). Kidney Int1996; 49: 578–597[ISI][Medline]
  2. Wolf G, Neilson EG. Angiotensin II as a renal growth factor. J Am Soc Nephrol1993; 3: 1531–1540[Abstract]
  3. Kaneto H, Morrissey J, Mccracken R, Reyes A, Klahr S. Enalapril reduces collagen type IV synthesis and expansion of the interstitium in the obstructed rat kidney. Kidney Int1994; 45: 1637–1647[ISI][Medline]
  4. Ishidoya S, Morrissey J, Mccracken R, Reyes A, Klahr S. Angiotensin II receptor antagonist ameliorates renal tubulointerstitial fibrosis caused by unilateral ureteral obstruction. Kidney Int1995; 47: 1285–1294[ISI][Medline]
  5. Ruiz-Ortega M, Gonzalez S, Seron D et al. ACE inhibition reduces proteinuria, glomerular lesions and extracellular matrix production in a normotensive rat model of immune complex nephritis. Kidney Int1995; 48: 1778–1791[ISI][Medline]
  6. Wu LL, Cox A, Roe CJ, Dziadek M, Cooper ME, Gilbert RE. Transforming growth factor ß1 and renal injury following subtotal nephrectomy in the rat: Role of the renin–angiotensin system. Kidney Int1997; 51: 1555–1567
  7. Ruiz-Ortega M, Gomez-Garre D, Alcazar R et al. Involvement of angiotensin II and endothelin on matrix protein production and renal sclerosis. J Hypertens1994; 12: S51–58[ISI]
  8. Ruiz-Ortega M, Egido J. Angiotensin II modulates cell growth-related events and synthesis of matrix proteins in renal interstitial fibroblasts. Kidney Int1997; 52: 1497–1510[ISI][Medline]
  9. Ruiz-Ortega M, Bustos C, Hernández-Presa MA, Lorenzo O, Plaza JJ, Egido J. Angiotensin II participates in mononuclear cell recruitment in the kidney through nuclear factor-kappa B activation and monocyte chemoattractant protein-1 gene expression. J Immunol1998; 161: 430–439[Abstract/Free Full Text]
  10. Ardaillou R, Chansel D. Synthesis and effects of active fragments of angiotensin II. Kidney Int1997; 52: 1458–1468[ISI][Medline]
  11. Klahr S, Schreiner G, Ichikawa I. The progression of renal disease. N Engl J Med1988; 318: 1657–1666[Abstract]
  12. Border WA, Rouslahti E. Transforming growth factor-ß in disease: The dark side of tissue repair. J Clin Invest1992; 90: 1–7[ISI][Medline]
  13. Shimada K, Yakazi Y. Binding sites of angiotensin II in human mononuclear leukocytes. J Biochem1978; 84: 1013–1020[Abstract]
  14. Mai M, Geiger H, Hilgers KF et al. Early interstitial changes in hypertension-induced renal injury. Hypertension1993; 22: 754–765[Abstract]
  15. Johnson RJ, Alpers CE, Yoshimura A et al. Renal injury from angiotensin II-mediated hypertension. Hypertension1994; 19: 464–474[Abstract]
  16. Wolf G, Ziyadeh FN, Thaiss F et al. Angiotensin II stimulates expression of the chemokines RANTES in rat glomerular endothelial cells. Role of the angiotensin type 2 receptor. J Clin Invest1997; 100: 1047–1058[Abstract/Free Full Text]
  17. Goetzel EJ, Klickstein LB, Watt KWK, Wintroub BU. The preferential human mononuclear leukocyte chemotactic activity of the substituent tetrapeptides of angiotensin II. Biochem Biophys Res Commun1980; 97: 1097–1101[ISI][Medline]
  18. Weinstock JV, Kassab JT. Angiotensin II stimulation of granuloma macrophages phagocytosis and actin polymerization in murine schistosomiasis mansoni. Cell Immunol1984; 89: 46–54[ISI][Medline]
  19. Hanh AW, Jonas U, Bühler FR, Resink TJ. Activation of human peripheral monocytes by angiotensin II. FEBS Lett1994; 347: 178–180[ISI][Medline]
  20. Gräfe M, Auch-Schwelk W, Graf K et al. Induction of the adhesion molecule E-selectin in human cardiac endothelial cells by angiotensin II. Circulation1993; 88: 1316 (Abs.)
  21. Nikolic-Paterson DJ, Lan HY, Hill PA, Atkins RC. Macrophages in renal injury. Kidney Int1994; 45: S79–82[ISI]
  22. Brunner HR. ACE inhibitors in renal disease. Kidney Int1992; 42: 463–479[ISI][Medline]
  23. Ishidoya S, Morrissey J, McCracken R, Reyes A, Klahr S. Angiotensin II receptor antagonist ameliorates renal tubulointerstitial fibrosis caused by unilateral ureteral obstruction. Kidney Int1995; 47: 1285–1294[ISI][Medline]
  24. Schlöndorf D. The role of chemokines in the initiation and progression of renal disease. Kidney Int1995; 47: S44–47[ISI]
  25. Gomez-Chiarri M, Ortiz A, Serón D, Gonzalez E, Egido J. The intercrine superfamily and renal disease. Kidney Int1993; 43: S81–84
  26. Prodjosudjadi W, Gerritsma JSJ, van Es LA, Daha MR, Bruijn JA. Monocyte chemoattractant protein-1 in normal and diseased human kidneys: an immunohistochemical analysis. Clin Nephrol1995; 44: 148–155[ISI][Medline]
  27. Tang WW, Qi M, Warren JS. Monocyte chemoattractant protein-1 mediates glomerular macrophage infiltration in anti-GBM Ab GN. Kidney Int1996; 50: 665–671[ISI][Medline]
  28. Wenzel U, Schneider A, Valente AJ et al. Monocyte chemoattractent protein-1 mediates monocyte/macrophage influx in anti-thymocyte antibody-induced glomerunephritis. Kidney Int1997; 51: 770–776[ISI][Medline]
  29. Hisada Y, Sugaya T, Yamanouchi M et al. Angiotensin II plays a pathogenic role in immune-mediated renal injury in mice. J Clin Invest1999; 103: 627–635[Abstract/Free Full Text]
  30. Bernstein KE, Berk BC. The biology of angiotensin II receptors. Am J Kidney Dis1993; 22: 745–754[ISI][Medline]
  31. Wolf G, Schneider A, Helmchen UM, Stahl RA. AT1-receptor antagonists abolish glomerular MCP-1 expression in a model of mesangial proliferative glomerulonephritis. Exp Nephrol1998; 6: 112–120[ISI][Medline]
  32. Morrissey JJ, Klahr S. Differential effects of ACE and AT1 receptor inhibition on chemoattractant and adhesion molecule synthesis. Am J Physiol1998; 274: F580–586[Abstract/Free Full Text]
  33. Hernandez-Presa M, Bustos C, Ortego M, Tuñón J, Ruiz-Ortega M, Egido J. Angiotensin converting enzyme inhibition prevents arterial NF{kappa}B activation, MCP-1 expression and macrophage infiltration in a rabbit model of early accelerated atherosclerosis. Circulation1997; 95: 1532–1541[Abstract/Free Full Text]
  34. Capers Q, Alexander RW, Lou P et al. Monocyte chemoattractant protein-1 expression in aortic tissues of hypertensive rats. Hypertension1997; 30: 1397–1402[Abstract/Free Full Text]
  35. Hamaguchi A, Kim S, Yano M, Yamanaka S, Iwao H. Activation of glomerular mitogen-activated kinases in angiotensin II-mediated hypertension. J Am Soc Nephrol1998; 9: 372–380[Abstract]
  36. Marrero MB, Schieffer B, Paxton WG et al. Direct stimulation of Jak/STAT pathway by the angiotensin II AT1 receptor. Nature1995; 375: 247–250[ISI][Medline]
  37. Takeuchi K, Nakemura N, Cook NS, Pratt RE, Dzau VJ. Angiotensin II can regulate gene expression by the AP-1 binding sequence via a protein kinase C-dependent pathway. Biochem Bioph Res Commun1990; 172: 1189–1192[ISI][Medline]
  38. Nahman NS, Rothe KL, Falkenhain ME et al. Angiotensin II induction of fibronectin biosynthesis in cultured human mesangial cells: association with CREB transcription factor activation. J Lab Clin Med1996; 127: 599–611[ISI][Medline]
  39. Barnes PJ, Karin M. Nuclear factor-kB. A pivotal transcription factor in chronic inflammatory diseases. N Engl J Med1997; 336: 1066–1071[Free Full Text]
  40. Beauparlant P, Hiscott J. Biological and biochemical inhibitors of the NF-{kappa}B/rel proteins and cytokine synthesis. Cytokine Growth Factor Rev1996; 7: 175–190[Medline]
  41. Wendt T, Zhang YM, Bierhaus A et al. Tissue factor expression in an animal model of hydronephrosis. Nephrol Dial Transplant1995; 10: 1820–1828[Abstract]
  42. Morrissey JJ, Klahr S. Enalapril decreases nuclear factor kappa B activation in the kidney with ureteral obstruction. Kidney Int1997; 52: 926–933[ISI][Medline]
  43. Ruiz-Ortega M, Lorenzo O, Egido. Angiotensin II activates nuclear factor kappa B via AT1 and AT2 receptors in the kidney. Am J Hypertens1999; 12: 25A
  44. Linder V, Collins T. Expression of NF-{kappa}B and I{kappa}B by aortic endothelium in an arterial injury model. Am J Pathol1996; 148: 427–438[Abstract]
  45. Moriyama T, Fujibayashi M, Fujiwara Y et al. Angiotensin II stimulates interleukin-6 release from cultured mouse mesangial cells. J Am Soc Nephrol1995; 6: 95–101[Abstract]
  46. Brasier Ar, Li J. Mechanisms for inducible control of angiotensinogen gene transcription. Hypertension1996; 27: 465–475[Abstract/Free Full Text]
  47. Rovin BH, Dickerson JA, Tan LC, Hebert CA. Activation of nuclear factor-kB correlates with MCP-1 expression by human mesangial cells. Kidney Int1995; 48: 1263–1271[ISI][Medline]
  48. Klahr S, Morrissey JJ. Comparative study of ACE inhibitors and angiotensin II receptor antagonists in interstitial scarring. Kidney Int Suppl1997; 63: S111–114[Medline]
  49. Stoll M, Steckelings M, Paul M, Bottari SP, Metzger R, Unger T. The angiotensin AT2-receptor mediates inhibition of cell proliferation in coronary endothelial cells. J Clin Invest1995; 95: 651–657[ISI][Medline]
  50. Yamada T, Horiuchi M, Dzau VJ. Angiotensin II type 2 receptor mediates programmed cell death. Proc Natl Acad Sci USA1996; 93: 156–160[Abstract/Free Full Text]
  51. Zini S, Fournie-Zaluski MC, Chauvel E, Roques BP, Corvol P, Llorens-Cortes C. Identification of metabolic pathways of brain angiotensin II and III using specific aminopeptidase inhibitors: predominant role of angiotensin III in the control of vasopressin release. Proc Natl Acad Sci USA1996; 93: 11968–11973[Abstract/Free Full Text]
  52. Kerins DM, Hao Q, Vaughan DE. Angiotensin induction of PAI-1 expression in endothelial cells is mediated by the hexapeptide angiotensin IV. J Clin Invest1995; 96: 2515–2520[ISI][Medline]
  53. Terui J, Tamoto K, Sudo J. Proteinuric potentials of angiotensin II, (des-Asp1)-angiotensin II, and (des-Asp1, des-Arg2)-angiotensin II in rats. Biol Pharm Bull1994; 17: 1516–1518[ISI][Medline]
  54. Ruiz-Ortega M, Lorenzo O, Egido J. Angiotensin III upregulates genes involved in kidney damage in cultured mesangial cells and renal interstitial fibroblast. Kidney Int1998; 54: S41–45[ISI]