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Comparative effects of ACE inhibition and angiotensin II receptor blockade in the prevention of renal damage

2002; Elsevier BV; Volume: 62; Linguagem: Inglês

10.1046/j.1523-1755.62.s82.5.x

1523-1755

Saulo Klahr, Jeremiah J. Morrissey,

Hormonal Regulation and Hypertension

Comparative effects of ACE inhibition and angiotensin II receptor blockade in the prevention of renal damage. Angiotensin II (Ang II) regulates a number of genes associated with progression of renal disease. The regulation of gene expression by Ang II occurs through specific receptors that are linked to changes in the activity of transcription factors within the nucleus of target cells. In particular, members of the nuclear factor-κB family of transcription factors are activated, which in turn fuels at least two autocrine reinforcing loops that amplify Ang II and tumor necrosis factor-α formation. Angiotensin converting enzymes (ACE) inhibitors and angiotensin antagonists (AIIAs) differ both pharmacokinetically and pharmacodynamically in patients with end-stage renal disease (ESRD). Several ACE inhibitors (such as captopril, enalapril and lisinopril) are dialyzable, whereas all of the AIIAs studied are not. Dose titration may be necessary when administering ACE inhibitors to patients with renal failure (ESRD), but is rarely a consideration when AIIAs are used. Comparative effects of ACE inhibition and angiotensin II receptor blockade in the prevention of renal damage. Angiotensin II (Ang II) regulates a number of genes associated with progression of renal disease. The regulation of gene expression by Ang II occurs through specific receptors that are linked to changes in the activity of transcription factors within the nucleus of target cells. In particular, members of the nuclear factor-κB family of transcription factors are activated, which in turn fuels at least two autocrine reinforcing loops that amplify Ang II and tumor necrosis factor-α formation. Angiotensin converting enzymes (ACE) inhibitors and angiotensin antagonists (AIIAs) differ both pharmacokinetically and pharmacodynamically in patients with end-stage renal disease (ESRD). Several ACE inhibitors (such as captopril, enalapril and lisinopril) are dialyzable, whereas all of the AIIAs studied are not. Dose titration may be necessary when administering ACE inhibitors to patients with renal failure (ESRD), but is rarely a consideration when AIIAs are used. Intrarenal angiotensin II (Ang II) has important effects on renal function and urinary sodium excretion and, via these local actions, on blood pressure regulation. Angiotensin-converting enzyme inhibitor (ACE I) treatment has been found to be renoprotective in patients with a variety of chronic renal diseases as well as in diabetic patients with nephropathy. Although both ACE I and angiotensin subtype 1 receptor antagonists (AT1RA) are effective in inhibiting renin-angiotensin system (RAS), they differ in their effects on the components of the system. Inhibition of ACE results in a decreased conversion of Ang I to Ang II, and a compensatory rise in renin levels due to the loss of negative feedback inhibition by juxtaglomerular apparatus cells (JGA). In contrast, AT1RA produce elevation in both renin and Ang II because normal feedback inhibition of JGA cells through stimulation of angiotensin II subtype 1 (AT1) receptors is blocked. These differences in the level of inhibition may have implications for the therapeutic effects of AT1RA as compared to ACE I. ACE I reduces only ACE-dependent Ang II production, whereas AT1RA blocks the effect of Ang II from any source at the receptor level. In the presence of ACE inhibition Ang II may be produced by other proteases, including chymase and other serine proteases. It is known that there are at least two subtypes of AT receptors. Blockade of the AT1 receptors in the presence of Ang II levels may result in the stimulation of subtype 2 (AT1) receptors. AT1 receptors mediate most of the known effects of Ang II such as vasoconstriction, up-regulation of aldosterone synthesis and its release, and renal tubule sodium and water reabsorption. Most of the studies in models of chronic renal disease indicate that treatment with AT1RA affords renal protection that is comparable to that observed with ACE inhibition. In the last twenty years, there has been a substantial increase in the number of patients treated for end-stage renal disease (ESRD) in the United States1US Renal Data System USRDS 2001 Annual Data Report. National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Disease, Bethesda2001: 305-323Google Scholar. The reasons for this increase are not firmly established. There are consistent and significant differences in the incidence rate of ESRD in the various age, sex, and ethnic groups. The prevalence and incidence of chronic renal dysfunction is suspected to be even greater than that of ESRD2Perneger T.V. Klag M.J. Feldman H.I. Whelton P.K. Projections of hypertension-related renal disease in middle-aged residents of the United States.JAMA. 1993; 269: 1272-1277Crossref PubMed Scopus (74) Google Scholar; however, no nationally representative data are available on the prevalence of renal dysfunction as estimated by serum creatinine levels in the US population. A report by Jones et al described the distribution of serum creatinine levels by sex, age, and ethnic group in a representative sample of the US population3Jones C.A. McQuillan G.M. Kusek et al.Serum creatinine levels in the US population: Third National Health and Nutrition Examination Survey.Am J Kidney Dis. 1998; 32: 992-999Abstract Full Text PDF PubMed Scopus (450) Google Scholar. Serum creatinine level was evaluated in the third National Health and Nutrition Examination Survey (NHANES III) in 18,723 participants aged 12 years and older who were examined between 1988 and 1994. The mean serum creatinine value was 0.96 mg/dL for women in the United States and 1.16 mg/dL for men. Overall, among the US noninstitutionalized population, 10.9 million people are estimated to have creatinine values of 1.5 mg/dL or greater, 3.0 million have values of 1.7 mg/dL or greater, and 0.8 million have serum creatinine levels of 2.0 mg/dL or greater. In 1968 Risdon, Sloper and De Wardener made the seminal observation that no correlation could be found between the degree of histologic glomerular damage and the decline in renal function, as assessed by glomerular filtration rate (GFR)4Risdon R.A. Sloper J.C. De Wardener H.E. Relationship between renal function and histological changes found in renal-biopsy specimens from patients with persistent glomerular nephritis.Lancet. 1968; 17: 363-366Abstract Google Scholar. However, they did find a positive correlation between the histological presence of tubular atrophy and a decrease in GFR. Other investigators also reported that impaired renal function correlated best with structural changes in the renal tubulointerstitium5Striker G.E. Schainuck L.I. Cutler R.E. Benditt E.P. Structural-functional correlations in renal diseases. I. A method for assaying and classifying histopathologic changes in renal disease.Hum Pathol. 1970; 1: 615-630Abstract Full Text PDF PubMed Scopus (126) Google Scholar,6Schainuck L.I. Striker G.E. Cutler R.E. Benditt E.P. Structural-functional correlations in renal disease. II: The correlations.Hum Pathol. 1970; 1: 631-641Abstract Full Text PDF PubMed Scopus (424) Google Scholar. Interstitial fibrosis is a common feature of long-term ureteral obstruction and other models of renal failure. The process of fibrosis, in part, represents an imbalance between deposition of extracellular matrix (ECM) material and chemoattractant of infiltrating cells. Renal proximal cells and macrophages are a potent source of an array of factors such as Ang II, transforming growth factor-beta (TGF-β), interleukin-9 (IL-9), interleukin-6 (IL-6), fibroblast growth factor (FGF), tumor necrosis factor-alpha (TNF-α), and platelet-derived growth factor (PDGF). These growth factors serve as important regulators of cell growth and differentiation7Diamond J.R. Ricardo S.D. Klahr S. Mechanisms of interstitial fibrosis in obstructive nephropathy.Semin Nephrol. 1998; 18: 594-602PubMed Google Scholar. Many renal diseases are driven by the intercrine, autocrine, paracrine and endocrine effects of angiotensin II. Administration of an ACE inhibitor or an angiotensin II (AT1) receptor antagonists to animals with a diversity of models of renal disease ameliorate the increase in interstitial volume and attenuate the expression of TGF-β1 in tubular cells, decrease the production of extracellular matrix protein, activation of nuclear factor-kappa B (NF-κB), proliferation of fibroblasts, and conversion of their phenotype to myofibroblasts. In a model of ureteral obstruction a monocyte/macrophage infiltration was present. Such infiltration was markedly decreased in the obstructive kidney of rats treated with ACE inhibitor. This effect may be the result of a greater generation of nitric oxide (NO) related to increased levels of bradykinin during ACE inhibition8Morrissey J.J. Ishidoya S. McCracken R. Klahr S. Nitric oxide generation ameliorates the tubulointerstitial fibrosis of obstructive nephropathy.J Am Soc Nephrol. 1996; 7: 2202-2212PubMed Google Scholar. Angiotensin II, the primary effector of the renin-angiotensin system (RAS), is produced both systemically and locally in various tissues, including the vessel wall and the heart. This vasoactive substance binds to at least two high-affinity cellular receptors, designated the Ang II type 1 (AT1) receptor and the Ang II type 2 (AT2) receptor. Stimulation of the AT1 receptor is associated with vasoconstriction and with a hypertrophic or hyperplastic growth response in fibroblasts and myocytes, whereas stimulation of the AT2 receptor appears to be vasodilatory and antiproliferative or pro-apoptotic. Most of the pathophysiologic effects of Ang II, such as vasoconstriction, fibrosis, and thrombosis, can be inhibited by specific AT1 receptor blockade. Administration of an ACE inhibitor or an angiotensin II receptor (AT1) antagonist, to rats with unilateral ureteral obstruction (UUO), ameliorated the increase in interstitial volume and attenuated the increased expression of TGF-β1 in tubular cells, the increased production of extracellular matrix protein, the activation of NF-κB, the proliferation of fibroblasts, and the conversion of their phenotype to myofibroblasts Table 19Klahr S. Morrissey J. Comparative study of ACE inhibitors and angiotensin II receptor antagonists in interstitial scarring.Kidney Int. 1997; 52: S111-S114PubMed Google Scholar. A monocyte/macrophage infiltrate was present in the obstructed kidney of untreated rats and in the obstructed kidney of rats treated with the AT1 receptor antagonist. By contrast, this infiltrate was markedly decreased in the obstructed kidney of rats treated with an ACE inhibitor. This difference may be due to greater generation of NO related to increased levels of bradykinin during ACE inhibition10Reyes A.A. Porras B.H. Chasalow F.I. Klahr S. L-arginine decreases the infiltration of the kidney by macrophages in obstructive nephropathy and puromycin-induced nephrosis.Kidney Int. 1994; 45: 1346-1354Abstract Full Text PDF PubMed Scopus (67) Google Scholar. In fact, rats with unilateral obstruction given both an ACE inhibitor and L-arginine analog N-nitro-L-arginine methyl ester (L-NAME; an inhibitor of NO formation) had a substantial macrophage infiltrate. Administration of L-arginine in the drinking water significantly blunted the increases in interstitial volume, monocyte infiltration, interstitial collagen IV, and α-smooth muscle actin expression11Ishidoya S. Morrissey J. McCracken R. Klahr S. Delayed treatment with enalapril halts tubulointerstitial fibrosis in rats with obstructive nephropathy.Kidney Int. 1996; 49: 1110-1119Abstract Full Text PDF PubMed Scopus (155) Google Scholar. However, in contrast to ACE inhibitors, arginine administration did not decrease the expression of TGF-β1 mRNA in the kidney with ureteral ligation. We also found a tenfold increase in tissue inhibitors of metalloproteinase (TIMP-1) mRNA in the obstructed kidney. Administration of an ACE inhibitor blunted this increase by 40% (P < 0.001). The addition of L-NAME to the ACE inhibitor prevented the decrease in TIMP-1 mRNA. A common denominator of the beneficial effects of ACE inhibition or arginine and the deleterious effects of L-NAME during ACE inhibition may be a result of the increased or decreased generation of NO10Reyes A.A. Porras B.H. Chasalow F.I. Klahr S. L-arginine decreases the infiltration of the kidney by macrophages in obstructive nephropathy and puromycin-induced nephrosis.Kidney Int. 1994; 45: 1346-1354Abstract Full Text PDF PubMed Scopus (67) Google Scholar,11Ishidoya S. Morrissey J. McCracken R. Klahr S. Delayed treatment with enalapril halts tubulointerstitial fibrosis in rats with obstructive nephropathy.Kidney Int. 1996; 49: 1110-1119Abstract Full Text PDF PubMed Scopus (155) Google Scholar.Table 1Effect of ACE inhibitors or angiotensin II receptor antagonists on various parameters associated with renal interstitial fibrosis in obstructive nephropathyAT1AT2ParameterUntreatedACE inhibitorReceptor antagonistInterstitial volume++++++++++Monocytes/macrophages+++++++++++++Transforming growth factor-β+++++++++Fibroblast proliferation++++++++++Myofibroblast phenotype+++++++Clusterin+++++++++Nuclear factor-κB activation++++++++Values represent a semiquantitative assessment of response during obstructive nephropathy. A value of (++++) is the maximum response. A value of (0) would indicate no change from normal; however, in each instance there is an increase in that parameter from normal. (Reproduced with permission from Kidney International 52(Suppl 63):S11–S114, 1997.) Open table in a new tab Values represent a semiquantitative assessment of response during obstructive nephropathy. A value of (++++) is the maximum response. A value of (0) would indicate no change from normal; however, in each instance there is an increase in that parameter from normal. (Reproduced with permission from Kidney International 52(Suppl 63):S11–S114, 1997.) In these previously mentioned studies, the ACE inhibitor was administered before or concomitant with the onset of ureteral obstruction. We also have examined the effects of ACE inhibition after three or five days of established UUO in rats. Delayed administration of an ACE inhibitor slowed and in several instances halted the progression of fibrosis in the tubulointerstitium of the kidney with ureteral ligation. Pharmacological maneuvers that reduce angiotensin II (ACE inhibitors) or interfere with its action (AT1 receptor antagonists) blunt NF-κB activation and slow the progression of renal disease. Although AT2 receptor inhibition decreases NF-κB activation, the effect may be on NF-κB dimers that are different from those affected through AT1 receptors12Morrissey J. Klahr S. Transcription factor NF-kappa B regulation of renal fibrosis during ureteral obstruction.Semin Nephrol. 1998; 18: 603-611PubMed Google Scholar. Indeed, AT2 receptor inhibition in rats or AT2 receptor knockout in mice exacerbates renal fibrosis consequent to ureteral obstruction. Pharmacological maneuvers that reduce the activation of certain NF-κB isotypes may extrinsically blunt angiotensin II-mediated effects and also slow the progression of renal disease. In summary, Ang II regulates a number of genes associated with progression of renal disease. The regulation of gene expression by Ang II occurs through specific receptors that are ultimately linked to changes in the activity of transcription factors within the nucleus of target cells. In particular, members of the NF-κB family of transcription factors are activated, which in turn fuels at least two autocrine reinforcing loops that amplify angiotensin II and TNF-α formation Figure 1. This amplification of the angiotensin II and TNF-α signals to the same cells in an autocrine manner or to adjacent cells in a paracrine manner further amplify NF-κB activation within the kidney. This leads to fibroblast proliferation and subsequent differentiation into myofibroblasts. Furthermore, tubular epithelial cells are stimulated to produce chemoattractants and adhesion proteins to cause an inflammatory response, leading to monocyte-macrophage infiltration. The tubule cells also produce profibrotic cytokines, leading to an overproduction of extracellular matrix proteins by all cell types. The net result is fibrosis of the tubulointerstitium and progression of renal disease. Angiotensin converting enzyme inhibitors and angiotensin II antagonists (AIIAs) are pharmacokinetically and pharmacodynamically distinct. These compounds appear to be comparable, however, in their antiproteinuric effects. The antagonist losartan is the only drug in its class capable of lowering uric acid concentrations, a process accomplished by the ability of this compound to inhibit directly tubule reabsorption of uric acid. The change in GFR in a kidney that depends on Ang II for its function is greater with ACE inhibitors than with AIIAs. This difference is partly related to the ability of ACE inhibitors to increase bradykinin levels (a phenomenon that is not observed with AIIAs), thereby decreasing efferent arteriolar tone. Another contrast between ACE inhibitors and AIIAs is the pharmacokinetic profiles of the drugs in each class. With the exception of fosinopril and trandolapril, ACE inhibitors are cleared mainly by the kidney. AIIAs are predominantly cleared by the liver or by the liver and kidney. AIIAs, therefore, do not accumulate systemically when repetitively doses in patients with renal failure. Angiotensin converting enzyme inhibitors and AIIAs differ both pharmacokinetically and pharmacodynamically in patients with ESRD. ACE inhibitors are associated with anaphylactoid dialyzer reactions (for example, immediate hypersensitivity reactions), particularly when polysulfone dialyzers are used. Anaphylactoid dialyzer reactions have not been observed in patients given AIIAs. Residual renal function may change less often with AIIAs, partly because of the absence of a bradykinin effect on the efferent arteriole. There is a difference between ACE inhibitors and AIIAs is their respective dialyzability. Several ACE inhibitors (captopril, enalapril, and lisinopril) are dialyzable, whereas all of the AIIAs studied are not. Dose titration may be necessary when administering ACE inhibitors to patients with renal failure ESRD, but is rarely a consideration when AIIAs are used. In patients with non-dialysis-dependent chronic renal failure, hyperkalemia may occur less often with AIIAs than with ACE inhibitors, although the reason for this is unclear. The occurrence of hyperkalemia in ESRD patients with either an ACE inhibitor or an AIIA, though not yet systematically studied, most be regarded as a potential serious complication. The plasma kallikrein-kinin system was recognized more than 40 years ago13Schmaier A.H. The plasma kallikrein-kinin system counterbalances the renin-angiotensin system.J Clin Invest. 2002; 109: 1007-1009Crossref PubMed Scopus (99) Google Scholar. It was initially thought that this system contributed to physiologic homeostasis. To date there have been few animal models in which the role of plasma kallikrein-kinin can be studied. One such model is the bradykin B2 receptor knockout mouse (BKB2 R-1). Mice with this defect have cardiac hypertrophy, dilation of the heart chambers and increased left ventricular end-diastolic pressure, and they show exaggerated vasopressin responses to angiotensin II14Yang X.P. Liu Y.H. Mehta D. et al.Diminished cardioprotective response to inhibition of angiotensin-converting enzyme and angiotensin II type 1 receptor in B(2) kinin receptor gene knockout mice.Circ Res. 2001; 88: 1072-1079Crossref PubMed Scopus (109) Google Scholar. In the presence of Ang II infusion, these animals have increased blood pressure and reduced renal blood flow. Plasma kallikrein converts prorenin to renin and renin converts angiotensinogen to angiotensin I. ACE converts inactive angiotensin I to the vasoconstrictor angiotensin II. Angiotensin II stimulates plasminogen activator inhibitor 1 (PAI1) release from endothelial cells. At the same time ACE degrades bradykinin into bradykinin (1-7) or bradykinin (1-5), a peptide with thrombin inhibitory activity. Prolylcarboxy peptidase degrades angiotensin II or angiotensin I to the vasodilating peptide angiotensin II (1-7). Angiotensin II (1-7) stimulates NO and prostaglandins, which potentiates the effect of bradykinin. Diabetes mellitus is increasing in prevalence and is currently estimated to be about 7% of the United States. Diabetes accounts for 45% of the patients in ESRD in the United States. Two studies published in the New England Journal of Medicine indicate that losartan15Brenner B.M. Cooper M.E. de Zeeuw D. et al.Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy.N Engl J Med. 2001; 345: 861-869Crossref PubMed Scopus (5795) Google Scholar or irbesartan16Lewis E.J. Hunsicker L.G. Clarke W.R. et al.Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes.N Engl J Med. 2001; 345: 851-860Crossref PubMed Scopus (4761) Google Scholar confers significant benefit in patients with type 2 diabetes and nephropathy. Both losartan and irberstan lead to significant improvement in renal outcomes, indicating that these Ang II receptor blockers slow the progression of nephropathy in patients with type 2 diabetes, independently of their capacity to lower the systemic blood pressure.