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Why we block angiotensin II
Kidney International, Vol. 58 (2000), pp. 458–459
EDITORIAL
Why we block angiotensin II Current use of angiotensin II (Ang II) blocking agents to slow renal disease progression provides an example of successful interaction between laboratory and clinical investigation. Studies showing that converting enzyme inhibitors prevented remnant glomerular injury in rats with reduced nephron number prompted trials of these agents in patients with renal insufficiency [1]. The success of these trials in turn has stimulated further studies of the role of Ang II in experimental disease. The goal of these studies, as exemplified by the work of Haugen, Croatt and Nath, reported in this issue, is to improve clinical therapy [2]. Hopefully, reciprocating analysis of clinical and experimental data will steadily enhance our ability to treat progressive renal diseases. How can the current round of experimental studies guide future clinical efforts? One way is to provide a more logical basis for the prescription of Ang II blocking drugs. Trials in clinical renal disease for the most part have employed drug doses shown effective in essential hypertension. Better understanding of the actions of Ang II in diseased kidneys might prompt trials of higher doses in some patients. Given the potential hazards of higher doses and the logistic demands of human trials, investigators reasonably may hesitate to undertake such trials without more experimental data to guide their design. Experimental studies of Ang II action also may guide future clinical efforts by identifying new targets for therapeutic intervention. Two general strategies have been employed for this purpose. The first is to treat animals or cultured cells with Ang II blocking agents and see what processes are suppressed. The second, as employed by Haugen et al, is to administer Ang II and see what processes are stimulated [2]. In essence, these authors began with the knowledge that Ang II causes renal injury, and sought to find out how it does so. As is often the case in studies of renal disease, they were guided by recent developments in the larger field of vascular biology. The finding that Ang II causes oxidative stress in smooth muscle cells prompted them to investigate whether Ang II causes a similar change in the kidney. They found that kidneys from rats given a dose of Ang II sufficient to cause hypertension and proteinuria exhibit increased lipid peroxidation, protein carbonyl content,
and activity of the oxidant-inducible enzyme, heme oxygenase. Having identified increased oxidative stress in the kidneys of Ang II-treated rats, Haugen et al attempted to dissect the association between angiotensin II, oxidative stress, and injury [2]. They approached this problem with unusual care. First, they addressed the question of whether oxidative stress is caused directly by Ang II or whether it is a secondary consequence of renal injury. Studies in the DOCA salt model showed that oxidative stress is not a common consequence of renal injury characterized by glomerular hypertension and proteinuria. Studies in cultured cells showed that Ang II increases heme oxygenase expression. The demonstration that Ang II infusion in vivo causes oxidative stress before renal injury becomes apparent would have been a desirable supplement to these studies. Even without such a demonstration, however, one is inclined to accept the authors’ conclusion that Ang II causes oxidative stress. Having found that Ang II causes oxidative stress, the authors addressed the more difficult question of whether oxidative stress contributes to injury. They would like to have determined whether preventing oxidative stress protects the kidney from Ang II-induced injury. Therapies to reduce oxidative stress, however, are limited. The authors therefore instead assessed the effect of a prooxidant diet. Their finding that this maneuver increased injury is consistent with the hypothesis that oxidative stress causes injury. However, it does not tell us how much of the Ang II-induced renal injury is attributable to oxidative stress, or whether Ang II blocking agents protect the kidney by reducing oxidative stress. The problem faced by Haugen et al in establishing the importance of a potential mechanism of Ang II-induced injury is encountered in all studies that examine the role of Ang II in renal disease [2]. Ang II increases systemic and glomerular capillary pressure. It also acts directly on renal cell types including smooth muscle cells, glomerular epithelial cells, and tubular epithelial cells. There is evidence that both the hemodynamic and the direct, cellular effects of Ang II can promote injury culminating in fibrotic renal disease [3, 4]. At present, one can argue in favor of the importance of one or another mechanism of injury based on the time course and ubiquity of changes observed in different disease models. However, rigorous demonstration of the importance of any of the individual effects of Ang II is not possible because Ang
Key words: progressive renal disease, oxidative stress, hypertension, kidney injury.
2000 by the International Society of Nephrology
458
Editorial
II blocking drugs counteract all of them. The development of animals in which elements of the renin-angiotensin system can be deleted locally in a controlled manner offers exciting hope of better understanding in the future [5]. In discussing any study of the mechanism(s) by which Ang II injures the kidney, it is worth remembering that we have little evidence that Ang II levels are increased in kidney disease. Circulating renin and angiotensin levels are not increased in rats with a reduced nephron number, though Ang II blockade has been repeatedly shown to protect against disease progression in these animals [6]. Of course it is possible that Ang II blockade works by counteracting an increase in Ang II concentration at some site within the kidney. Sodium restriction, however, markedly increases intrarenal Ang II levels without causing renal injury [7]. Recent studies by Verhagen et al have provided new insight into this intriguing paradox [8]. They found that Ang II receptor blockade largely prevented renal injury in rats made hypertensive by inhibition of nitric oxide synthase (NOS). Of note, neither circulating nor intrarenal Ang II levels were increased in these animals. This finding suggests that even normal Ang II levels can cause renal injury when countervailing forces are reduced. One question we should now ask is whether oxidant stress similar to that caused by Ang II infusion is induced by other injurious maneuvers. Evidence on this point has recently been reviewed by Haugen and Nath [9]. A related question that remains unanswered is whether Ang II blockade reduces oxidant stress in these different settings. In asking these questions we reveal both the strengths and the limitation of Ang II manipulation as an experimental tool. Over the last decade, innumerable new molecules and processes have been identified as potential contributors to renal injury. In most cases, however, the expression of these molecules and the activity of these processes are difficult to adjust experimentally. We have an unusual degree of control over Ang II activity. Moreover, we know that we can produce renal injury
459
by infusing Ang II and, in many cases, reduce renal injury by blocking Ang II. We therefore use Ang II to get a handle on other potential mediators of injury. If a process such as oxidant stress is increased by Ang II and reduced by Ang II blockade, our interest in it increases. In the end, of course, we want to know more about the process than how Ang II effects it. In particular, we want to know what happens when we block the process selectively. We hope that studies in which Ang II is manipulated, such as the one performed by Haugen et al [2], will help guide the development of more powerful pharmacologic and genetic interventions to slow the progression of renal disease. Timothy W. Meyer Palo Alto, California Correspondence to Timothy W. Meyer, M.D., Nephrology 111R, VA Palo Alto HCS, 3801 Miranda Ave., Palo Alto, California, 94304, USA E-mail: [email protected]
REFERENCES 1. Anderson S, Meyer TW, Rennke HG, Brenner BM: Control of glomerular hypertension limits glomerular injury in rats with reduced renal mass. J Clin Invest 76:612–619, 1985 2. Haugen EN, Croatt AJ, Nath KA: Angiotensin II induces renal oxidant stress in vivo and heme oxygenase-1 in vivo and in vitro. Kidney Int 58:144–152, 2000 3. Levy BI: The potential role of angiotensin II in the vasculature. J Hum Hypertens 12:283–287, 1998 4. Diamond JR, Ricardo SD, Klahr S: Mechanisms of interstitial fibrosis in obstructive nephropathy. Semin Nephrol 18:594–602, 1998 5. Stec DE, Sigmund CD: Modifiable gene expression in mice: Kidney specific deletion of a target gene via the cre-loxP system. Exp Nephrol 6:568–575, 1998 6. Rosenberg ME, Smith LJ, Corea-Rotter R, Hostetter TH: The paradox of the renin-angiotensin system in chronic renal disease. Kidney Int 45:403–410, 1994 7. Navar LG: Intrarenal production of angiotensin II. Semin Nephrol 17:412–422, 1997 8. Verhagen AMG, Braam B, Boer P, Grone H-J, Koomans HA, Joles JA: Losartan-sensitive renal damage caused by chronic NOS inhibition does not involve increased renal angiotensin II concentrations. Kidney Int 56:222–231, 1999 9. Haugen E, Nath KA: The involvement of oxidative stress in the progression of renal injury. Blood Purif 17:58–65, 1999
EDITORIAL
Why we block angiotensin II Current use of angiotensin II (Ang II) blocking agents to slow renal disease progression provides an example of successful interaction between laboratory and clinical investigation. Studies showing that converting enzyme inhibitors prevented remnant glomerular injury in rats with reduced nephron number prompted trials of these agents in patients with renal insufficiency [1]. The success of these trials in turn has stimulated further studies of the role of Ang II in experimental disease. The goal of these studies, as exemplified by the work of Haugen, Croatt and Nath, reported in this issue, is to improve clinical therapy [2]. Hopefully, reciprocating analysis of clinical and experimental data will steadily enhance our ability to treat progressive renal diseases. How can the current round of experimental studies guide future clinical efforts? One way is to provide a more logical basis for the prescription of Ang II blocking drugs. Trials in clinical renal disease for the most part have employed drug doses shown effective in essential hypertension. Better understanding of the actions of Ang II in diseased kidneys might prompt trials of higher doses in some patients. Given the potential hazards of higher doses and the logistic demands of human trials, investigators reasonably may hesitate to undertake such trials without more experimental data to guide their design. Experimental studies of Ang II action also may guide future clinical efforts by identifying new targets for therapeutic intervention. Two general strategies have been employed for this purpose. The first is to treat animals or cultured cells with Ang II blocking agents and see what processes are suppressed. The second, as employed by Haugen et al, is to administer Ang II and see what processes are stimulated [2]. In essence, these authors began with the knowledge that Ang II causes renal injury, and sought to find out how it does so. As is often the case in studies of renal disease, they were guided by recent developments in the larger field of vascular biology. The finding that Ang II causes oxidative stress in smooth muscle cells prompted them to investigate whether Ang II causes a similar change in the kidney. They found that kidneys from rats given a dose of Ang II sufficient to cause hypertension and proteinuria exhibit increased lipid peroxidation, protein carbonyl content,
and activity of the oxidant-inducible enzyme, heme oxygenase. Having identified increased oxidative stress in the kidneys of Ang II-treated rats, Haugen et al attempted to dissect the association between angiotensin II, oxidative stress, and injury [2]. They approached this problem with unusual care. First, they addressed the question of whether oxidative stress is caused directly by Ang II or whether it is a secondary consequence of renal injury. Studies in the DOCA salt model showed that oxidative stress is not a common consequence of renal injury characterized by glomerular hypertension and proteinuria. Studies in cultured cells showed that Ang II increases heme oxygenase expression. The demonstration that Ang II infusion in vivo causes oxidative stress before renal injury becomes apparent would have been a desirable supplement to these studies. Even without such a demonstration, however, one is inclined to accept the authors’ conclusion that Ang II causes oxidative stress. Having found that Ang II causes oxidative stress, the authors addressed the more difficult question of whether oxidative stress contributes to injury. They would like to have determined whether preventing oxidative stress protects the kidney from Ang II-induced injury. Therapies to reduce oxidative stress, however, are limited. The authors therefore instead assessed the effect of a prooxidant diet. Their finding that this maneuver increased injury is consistent with the hypothesis that oxidative stress causes injury. However, it does not tell us how much of the Ang II-induced renal injury is attributable to oxidative stress, or whether Ang II blocking agents protect the kidney by reducing oxidative stress. The problem faced by Haugen et al in establishing the importance of a potential mechanism of Ang II-induced injury is encountered in all studies that examine the role of Ang II in renal disease [2]. Ang II increases systemic and glomerular capillary pressure. It also acts directly on renal cell types including smooth muscle cells, glomerular epithelial cells, and tubular epithelial cells. There is evidence that both the hemodynamic and the direct, cellular effects of Ang II can promote injury culminating in fibrotic renal disease [3, 4]. At present, one can argue in favor of the importance of one or another mechanism of injury based on the time course and ubiquity of changes observed in different disease models. However, rigorous demonstration of the importance of any of the individual effects of Ang II is not possible because Ang
Key words: progressive renal disease, oxidative stress, hypertension, kidney injury.
2000 by the International Society of Nephrology
458
Editorial
II blocking drugs counteract all of them. The development of animals in which elements of the renin-angiotensin system can be deleted locally in a controlled manner offers exciting hope of better understanding in the future [5]. In discussing any study of the mechanism(s) by which Ang II injures the kidney, it is worth remembering that we have little evidence that Ang II levels are increased in kidney disease. Circulating renin and angiotensin levels are not increased in rats with a reduced nephron number, though Ang II blockade has been repeatedly shown to protect against disease progression in these animals [6]. Of course it is possible that Ang II blockade works by counteracting an increase in Ang II concentration at some site within the kidney. Sodium restriction, however, markedly increases intrarenal Ang II levels without causing renal injury [7]. Recent studies by Verhagen et al have provided new insight into this intriguing paradox [8]. They found that Ang II receptor blockade largely prevented renal injury in rats made hypertensive by inhibition of nitric oxide synthase (NOS). Of note, neither circulating nor intrarenal Ang II levels were increased in these animals. This finding suggests that even normal Ang II levels can cause renal injury when countervailing forces are reduced. One question we should now ask is whether oxidant stress similar to that caused by Ang II infusion is induced by other injurious maneuvers. Evidence on this point has recently been reviewed by Haugen and Nath [9]. A related question that remains unanswered is whether Ang II blockade reduces oxidant stress in these different settings. In asking these questions we reveal both the strengths and the limitation of Ang II manipulation as an experimental tool. Over the last decade, innumerable new molecules and processes have been identified as potential contributors to renal injury. In most cases, however, the expression of these molecules and the activity of these processes are difficult to adjust experimentally. We have an unusual degree of control over Ang II activity. Moreover, we know that we can produce renal injury
459
by infusing Ang II and, in many cases, reduce renal injury by blocking Ang II. We therefore use Ang II to get a handle on other potential mediators of injury. If a process such as oxidant stress is increased by Ang II and reduced by Ang II blockade, our interest in it increases. In the end, of course, we want to know more about the process than how Ang II effects it. In particular, we want to know what happens when we block the process selectively. We hope that studies in which Ang II is manipulated, such as the one performed by Haugen et al [2], will help guide the development of more powerful pharmacologic and genetic interventions to slow the progression of renal disease. Timothy W. Meyer Palo Alto, California Correspondence to Timothy W. Meyer, M.D., Nephrology 111R, VA Palo Alto HCS, 3801 Miranda Ave., Palo Alto, California, 94304, USA E-mail: [email protected]
REFERENCES 1. Anderson S, Meyer TW, Rennke HG, Brenner BM: Control of glomerular hypertension limits glomerular injury in rats with reduced renal mass. J Clin Invest 76:612–619, 1985 2. Haugen EN, Croatt AJ, Nath KA: Angiotensin II induces renal oxidant stress in vivo and heme oxygenase-1 in vivo and in vitro. Kidney Int 58:144–152, 2000 3. Levy BI: The potential role of angiotensin II in the vasculature. J Hum Hypertens 12:283–287, 1998 4. Diamond JR, Ricardo SD, Klahr S: Mechanisms of interstitial fibrosis in obstructive nephropathy. Semin Nephrol 18:594–602, 1998 5. Stec DE, Sigmund CD: Modifiable gene expression in mice: Kidney specific deletion of a target gene via the cre-loxP system. Exp Nephrol 6:568–575, 1998 6. Rosenberg ME, Smith LJ, Corea-Rotter R, Hostetter TH: The paradox of the renin-angiotensin system in chronic renal disease. Kidney Int 45:403–410, 1994 7. Navar LG: Intrarenal production of angiotensin II. Semin Nephrol 17:412–422, 1997 8. Verhagen AMG, Braam B, Boer P, Grone H-J, Koomans HA, Joles JA: Losartan-sensitive renal damage caused by chronic NOS inhibition does not involve increased renal angiotensin II concentrations. Kidney Int 56:222–231, 1999 9. Haugen E, Nath KA: The involvement of oxidative stress in the progression of renal injury. Blood Purif 17:58–65, 1999