Authors’ reply:

Abstract

We thank Dr Morrissey for his insightful analysis and thoughtful comments related to our recent paper.1Nataraj C Oliverio M Mannon R Mannon P Audoly L Amuchastegui C Smithies O Coffman T Angiotensin II regulates cellular immune responses through a calcineurin-dependent pathway.J Clin Invest. 1999; 104: 1693-1701Crossref PubMed Scopus (256) Google Scholar Although the actions of the renin-angiotensin system (RAS) to modulate blood pressure and vascular functions are well established, our article is part of a growing body of literature that has identified another important function of this system: to regulate inflammation and immune responses. Teleologically, it is not clear why evolution has shaped this ancient hormone system to carry out such divergent and seemingly unrelated functions. Nonetheless, our experiments confirmed and extended a long line of studies that have identified pervasive expression of components of the RAS in immune and inflammatory cell types in a range of species. An important issue for the future will be to identify particular inflammatory responses in which the RAS plays a dominant role and, as a corollary, where pharmacologic inhibition of this system will have a major impact. Accumulating evidence suggests that organ transplantation is one such circumstance.A number of studies have shown beneficial effects of angiotensin-converting enzyme (ACE) inhibitors or AT1 receptor antagonists in experimental transplant models.2Amuchastegui C Azzillini N Mister M Pezzotta N Perico N Remuzzi G Chronic allograft nephropathy in the rat is improved by angiotensin II receptor blockade but not by calcium channel antagonism.J Am Soc Nephrol. 1998; 9: 1948-1955PubMed Google Scholar, 3Benediktsson H Chea R Davidoff A Paul L Antihypertensive drug treatment in chronic allograft rejection in the rat: Effect on structure and function.Transplantation. 1996; 62: 1634-1642Crossref PubMed Scopus (89) Google Scholar, 4Furukawa Y Matsumori A Hirozane T Sasayama S Angtiotensin II receptor antagonist TCV-116 reduces graft coronary artery disease and preserves graft status in a murine model.Circulation. 1996; 93: 333-339Crossref PubMed Scopus (72) Google Scholar, 5Kobayashi J Crawford S Backer C Zales V Takami H Hsueh C Huang L Mavroudis C Captopril reduces graft coronary artery disease in a rat heterotopic transplant model.Circulation. 1993; 88: 286-290Google Scholar, 6Mackenzie H Ziai F Nagano H Azuma H Troy J Rennke H Tilney N Brenner B Candesartan cilexetil reduces renal allograft injury in Fisher→Lewis rats.J Hypertension. 1997; 15: S21-S25Crossref Google Scholar Generally, these have been models of chronic rejection in which the intensity of the alloimmune response is relatively indolent. When ACE inhibitors and AT1 antagonists have been compared head-to-head, the responses have been similar, suggesting that the effects of the RAS to promote allograft injury are mediated through AT1 receptors.4Furukawa Y Matsumori A Hirozane T Sasayama S Angtiotensin II receptor antagonist TCV-116 reduces graft coronary artery disease and preserves graft status in a murine model.Circulation. 1996; 93: 333-339Crossref PubMed Scopus (72) Google Scholar The efficacy of RAS antagonists in these models has been impressive, reducing intimal proliferation and myocardial fibrosis in heart grafts4Furukawa Y Matsumori A Hirozane T Sasayama S Angtiotensin II receptor antagonist TCV-116 reduces graft coronary artery disease and preserves graft status in a murine model.Circulation. 1996; 93: 333-339Crossref PubMed Scopus (72) Google Scholar, 5Kobayashi J Crawford S Backer C Zales V Takami H Hsueh C Huang L Mavroudis C Captopril reduces graft coronary artery disease in a rat heterotopic transplant model.Circulation. 1993; 88: 286-290Google Scholar and ameliorating interstitial fibrosis and glomerulosclerosis in kidney grafts.2Amuchastegui C Azzillini N Mister M Pezzotta N Perico N Remuzzi G Chronic allograft nephropathy in the rat is improved by angiotensin II receptor blockade but not by calcium channel antagonism.J Am Soc Nephrol. 1998; 9: 1948-1955PubMed Google Scholar, 3Benediktsson H Chea R Davidoff A Paul L Antihypertensive drug treatment in chronic allograft rejection in the rat: Effect on structure and function.Transplantation. 1996; 62: 1634-1642Crossref PubMed Scopus (89) Google Scholar, 6Mackenzie H Ziai F Nagano H Azuma H Troy J Rennke H Tilney N Brenner B Candesartan cilexetil reduces renal allograft injury in Fisher→Lewis rats.J Hypertension. 1997; 15: S21-S25Crossref Google Scholar One interpretation of these experiments has been that angiotensin II promotes chronic rejection through its actions to stimulate vascular smooth muscle cell growth and hypertrophy7Owens G Control of hypertrophic versus hyperplastic growth of vascular smooth muscle cells.Am J Physiol. 1989; 257: H1755-H1765PubMed Google Scholar and to activate production of fibrinogenic cytokines such as transforming growth factor-β.8Klahr S Morrissey J Angtiotensin II and gene expression in kidney.Am J Kidney Dis. 1998; 31: 171-176Abstract Full Text Full Text PDF PubMed Scopus (123) Google Scholar Our studies and others suggest that some of the actions of angiotensin II in rejection may be through direct effects on the immune system.As outlined by Dr Morrissey, along with its effects on lymphocyte activation and proliferation, the RAS may modulate immune responses by promoting recruitment of immune cells into the site of inflammation. The potential role of angiotensin II in chemotaxis was originally suggested in a paper by Weinstock and Kassab,9Weinstock J Kassab J Chemotactic response of splenic mononuclear cells to angiotensin II in murine schistosomiasis.J Immunol. 1986; 137: 2020-2024PubMed Google Scholar who used a murine schistosomiasis model. Similarly, Kobayashi et al5 showed that treatment with an ACE inhibitor significantly reduced cellular infiltrates in rat cardiac allografts, an effect that might be explained by alterations in cell trafficking.5Kobayashi J Crawford S Backer C Zales V Takami H Hsueh C Huang L Mavroudis C Captopril reduces graft coronary artery disease in a rat heterotopic transplant model.Circulation. 1993; 88: 286-290Google Scholar Angiotensin II may enhance leukocyte recruitment to inflamed sites by virtue of its ability to upregulate adhesion molecule expression in endothelial cells.10Pastore L Tessitore A Martinotti S Toniato E Alesse E Bravi M Ferri C Desideri M Gulino A Antucci A Angiotensin II stimulates ICAM-1 expression by human vascular endothelial cells and increases soluble ICAM-1 release in vivo.Circulation. 1999; 100: 1646-1652Crossref PubMed Scopus (221) Google Scholar, 11Tummala P Chen X-L Sundell C Laursen J Hammes C Alexander W Harrison D Medford R Angiotensin II induces vascular cell adhesion molecule-1 expression in rat vasculature: A potenial link between the renin angiotensin system and atherosclerosis.Circulation. 1999; 100: 1223-1229Crossref PubMed Scopus (327) Google Scholar Our unpublished observations support this finding and suggest that AT1A receptors promote adhesion of mouse leukocytes to endothelial cells. Alternatively, as demonstrated by Hisada et al,12Hisada Y Sugaya T Yamanouchi M Uchida H Fujimura H Sakurai H Fukamizu A Murakami K Angiotensin II plays a pathogenic role in immune-mediated renal injury in mice.J Clin Invest. 1999; 103: 627-635Crossref PubMed Scopus (133) Google Scholar angiotensin II may stimulate chemotaxis and leukocyte adhesion indirectly, by inducing production of chemokines such as monocyte chemoattractant protein-1 (MCP-1).Although our studies focused on a potential role for angiotensin II in alloimmunity and in applications related to transplantation, it is plausible that the proinflammatory actions of the RAS may contribute to the pathogenesis of other cardiovascular disorders. For example, inflammation is recognized as a critical element in the development of atherosclerosis.13Ross R Atherosclerosis is an inflammatory disease.Am Heart J. 1999; 138 (part 2): S419-S420Abstract Full Text Full Text PDF PubMed Google Scholar Studies in mice have documented the efficacy of AT1 receptor blockers to retard atherogenesis.14Hayek T Attias J Coleman R Brodsky S Smith J Breslow J Keidar S The angiotensin-converting enzyme inhibitor, fosinopril, and the angiotensin II receptor antagonist, losartan, inhibit LDL oxidation and attenuate atherosclerosis independent of lowering blood pressure in apolipoprotein E deficient mice.Cardiovasc Res. 1999; 44: 579-587Crossref PubMed Scopus (145) Google Scholar, 15Keider S Attias J Smith J Breslow J Hayek T The angiotensin II receptor antagonist losartan inhibits LDL peroxidation and atherosclerosis in apolipoprotein E-deficient mice.Biochem Biophys Res Commun. 1997; 236: 622-625Crossref PubMed Scopus (128) Google Scholar These actions may explain some of the clinical efficacy of ACE inhibitors to prevent cardiovascular morbidity and mortality.16Francis G ACE inhibition in cardiovascular disease.N Engl J Med. 2000; 342: 201-202Crossref PubMed Scopus (80) Google Scholar We suggest that the actions of angiotensin II to promote inflammatory cell migration and activation may contribute to the pathogenesis of these pervasive vascular diseases. Moreover, gene targeting approaches may be useful in defining the discrete contributions of vascular versus immunologic effects of angiotensin II in these processes.As Dr Morrissey points out, we did not directly examine AT1B receptor mRNA expression in the splenocyte system that we used in our experiments. However, several lines of evidence suggest that AT1B receptors play little or no role in promoting lymphocyte proliferation. First, specific angiotensin receptors were easily detected on lymphocytes from wild-type animals, and most of these sites conformed to the pharmacologic profile of AT1 receptors. In contrast, no significant angiotensin II binding could be detected on lymphocytes from AT1A− /− mice, suggesting that AT1A receptors are the only angiotensin receptors that were expressed on these cells; we found no evidence for residual binding to AT1B receptors on splenocytes from AT1A− /− mice. In a mixed lymphocyte reaction (MLR) that used wild-type cells, losartan, an antagonist of both AT1A and AT1B receptors, reduced proliferation to levels that were similar to those observed in MLR with AT1A− /− responders. Furthermore, losartan caused no further inhibition of proliferative responses in AT1A− /− cells. Our conclusion from these data is that the AT1B receptor does not play a role in regulating lymphocyte function and that virtually all of the effects of angiotensin II to modulate lymphocyte proliferation are mediated by AT1A receptors.We would finally like to amplify one additional point that was made by Dr Morrissey regarding the possibility that multiple second messengers and transcription factors that may mediate the immunologic actions of angiotensin II. In our discussion, we emphasized the role of the calcineurin-nuclear factor of activated T cells (NFAT) pathway because of its well-characterized and dominant actions in transplant rejection.17Schreiber S Crabtree G The mechanism of action of cyclosporin A and FK506.Immunol Today. 1992; 13: 136-142Abstract Full Text PDF PubMed Scopus (1947) Google Scholar In addition, studies from Eric Olsen’s laboratory had recently established a connection between angiotensin II and the calcineurin-NFAT system in nonimmune cells.18Molkentin J Lu J-R Antos C Markham B Richardson J Robbins J Grant S Olson E A calcineurin-dependent transcriptional pathway for cardiac hypertrophy.Cell. 1998; 93: 215-228Abstract Full Text Full Text PDF PubMed Scopus (2191) Google Scholar We agree with Dr Morrissey that other second messengers and transcription factors also may be involved. The NF-kB system is one prime candidate, and the JAK/STAT kinase system19Marrero M Schieffer B Paxton W Heerdt L Berk B Delafontaine P Bernstein K Direct stimulation of Jak/STAT pathway by the angiotensin II AT1 receptor.Nature. 1995; 375: 247-250Crossref PubMed Scopus (649) Google Scholar is another. We believe that identification of the molecular signaling pathways that mediate the proinflammatory actions of angiotensin II will be a promising future area for investigation.What are the practical applications of our findings? Historically, transplant physicians have not been enthusiastic about using ACE inhibitors or AT1 receptor blockers in organ allograft recipients. The reasons for this lack of enthusiasm probably include the perception that these patients tend to have a volume-expanded, “low renin” form of hypertension and that ACE inhibitors may have detrimental effects on renal function in patients treated with calcineurin antagonists or in the presence of transplant artery stenosis. However, we believe that these agents may have unique beneficial actions in the transplant patient. For example, there is a disproportionately high burden of cardiovascular disease among transplant patients, and the positive influence of ACE inhibition on cardiovascular morbidity and mortality is now well established.16Francis G ACE inhibition in cardiovascular disease.N Engl J Med. 2000; 342: 201-202Crossref PubMed Scopus (80) Google Scholar Furthermore, there is compelling evidence in preclinical models that ACE inhibitors and AT1 receptor blockers prevent chronic nephropathy caused by calcineurin antagonists.20Burdmann E Andoh T Nast C Evan A Connors B Coffman T Lindsley J Bennett W Prevention of experimental cyclosporine-induced interstitial fibrosis by losartan and enalApril.Am J Physiol. 1995; 269: F-491-F499Google Scholar Our study shows that these agents also directly inhibit alloimmune responses. Finally, our data indicate that AT1 receptor antagonists may potentiate the immunosuppressive actions of calcineurin inhibitors. Combined treatment with angiotensin receptor blocker and calcineurin inhibitor may provide a strategy for reducing the dose of calcineurin inhibitor that is required to maintain adequate immunosuppression, thereby reducing the potential risk of long-term toxicity. Of course, the clinical relevance of these observations will need to be tested. We thank Dr Morrissey for his insightful analysis and thoughtful comments related to our recent paper.1Nataraj C Oliverio M Mannon R Mannon P Audoly L Amuchastegui C Smithies O Coffman T Angiotensin II regulates cellular immune responses through a calcineurin-dependent pathway.J Clin Invest. 1999; 104: 1693-1701Crossref PubMed Scopus (256) Google Scholar Although the actions of the renin-angiotensin system (RAS) to modulate blood pressure and vascular functions are well established, our article is part of a growing body of literature that has identified another important function of this system: to regulate inflammation and immune responses. Teleologically, it is not clear why evolution has shaped this ancient hormone system to carry out such divergent and seemingly unrelated functions. Nonetheless, our experiments confirmed and extended a long line of studies that have identified pervasive expression of components of the RAS in immune and inflammatory cell types in a range of species. An important issue for the future will be to identify particular inflammatory responses in which the RAS plays a dominant role and, as a corollary, where pharmacologic inhibition of this system will have a major impact. Accumulating evidence suggests that organ transplantation is one such circumstance. A number of studies have shown beneficial effects of angiotensin-converting enzyme (ACE) inhibitors or AT1 receptor antagonists in experimental transplant models.2Amuchastegui C Azzillini N Mister M Pezzotta N Perico N Remuzzi G Chronic allograft nephropathy in the rat is improved by angiotensin II receptor blockade but not by calcium channel antagonism.J Am Soc Nephrol. 1998; 9: 1948-1955PubMed Google Scholar, 3Benediktsson H Chea R Davidoff A Paul L Antihypertensive drug treatment in chronic allograft rejection in the rat: Effect on structure and function.Transplantation. 1996; 62: 1634-1642Crossref PubMed Scopus (89) Google Scholar, 4Furukawa Y Matsumori A Hirozane T Sasayama S Angtiotensin II receptor antagonist TCV-116 reduces graft coronary artery disease and preserves graft status in a murine model.Circulation. 1996; 93: 333-339Crossref PubMed Scopus (72) Google Scholar, 5Kobayashi J Crawford S Backer C Zales V Takami H Hsueh C Huang L Mavroudis C Captopril reduces graft coronary artery disease in a rat heterotopic transplant model.Circulation. 1993; 88: 286-290Google Scholar, 6Mackenzie H Ziai F Nagano H Azuma H Troy J Rennke H Tilney N Brenner B Candesartan cilexetil reduces renal allograft injury in Fisher→Lewis rats.J Hypertension. 1997; 15: S21-S25Crossref Google Scholar Generally, these have been models of chronic rejection in which the intensity of the alloimmune response is relatively indolent. When ACE inhibitors and AT1 antagonists have been compared head-to-head, the responses have been similar, suggesting that the effects of the RAS to promote allograft injury are mediated through AT1 receptors.4Furukawa Y Matsumori A Hirozane T Sasayama S Angtiotensin II receptor antagonist TCV-116 reduces graft coronary artery disease and preserves graft status in a murine model.Circulation. 1996; 93: 333-339Crossref PubMed Scopus (72) Google Scholar The efficacy of RAS antagonists in these models has been impressive, reducing intimal proliferation and myocardial fibrosis in heart grafts4Furukawa Y Matsumori A Hirozane T Sasayama S Angtiotensin II receptor antagonist TCV-116 reduces graft coronary artery disease and preserves graft status in a murine model.Circulation. 1996; 93: 333-339Crossref PubMed Scopus (72) Google Scholar, 5Kobayashi J Crawford S Backer C Zales V Takami H Hsueh C Huang L Mavroudis C Captopril reduces graft coronary artery disease in a rat heterotopic transplant model.Circulation. 1993; 88: 286-290Google Scholar and ameliorating interstitial fibrosis and glomerulosclerosis in kidney grafts.2Amuchastegui C Azzillini N Mister M Pezzotta N Perico N Remuzzi G Chronic allograft nephropathy in the rat is improved by angiotensin II receptor blockade but not by calcium channel antagonism.J Am Soc Nephrol. 1998; 9: 1948-1955PubMed Google Scholar, 3Benediktsson H Chea R Davidoff A Paul L Antihypertensive drug treatment in chronic allograft rejection in the rat: Effect on structure and function.Transplantation. 1996; 62: 1634-1642Crossref PubMed Scopus (89) Google Scholar, 6Mackenzie H Ziai F Nagano H Azuma H Troy J Rennke H Tilney N Brenner B Candesartan cilexetil reduces renal allograft injury in Fisher→Lewis rats.J Hypertension. 1997; 15: S21-S25Crossref Google Scholar One interpretation of these experiments has been that angiotensin II promotes chronic rejection through its actions to stimulate vascular smooth muscle cell growth and hypertrophy7Owens G Control of hypertrophic versus hyperplastic growth of vascular smooth muscle cells.Am J Physiol. 1989; 257: H1755-H1765PubMed Google Scholar and to activate production of fibrinogenic cytokines such as transforming growth factor-β.8Klahr S Morrissey J Angtiotensin II and gene expression in kidney.Am J Kidney Dis. 1998; 31: 171-176Abstract Full Text Full Text PDF PubMed Scopus (123) Google Scholar Our studies and others suggest that some of the actions of angiotensin II in rejection may be through direct effects on the immune system. As outlined by Dr Morrissey, along with its effects on lymphocyte activation and proliferation, the RAS may modulate immune responses by promoting recruitment of immune cells into the site of inflammation. The potential role of angiotensin II in chemotaxis was originally suggested in a paper by Weinstock and Kassab,9Weinstock J Kassab J Chemotactic response of splenic mononuclear cells to angiotensin II in murine schistosomiasis.J Immunol. 1986; 137: 2020-2024PubMed Google Scholar who used a murine schistosomiasis model. Similarly, Kobayashi et al5 showed that treatment with an ACE inhibitor significantly reduced cellular infiltrates in rat cardiac allografts, an effect that might be explained by alterations in cell trafficking.5Kobayashi J Crawford S Backer C Zales V Takami H Hsueh C Huang L Mavroudis C Captopril reduces graft coronary artery disease in a rat heterotopic transplant model.Circulation. 1993; 88: 286-290Google Scholar Angiotensin II may enhance leukocyte recruitment to inflamed sites by virtue of its ability to upregulate adhesion molecule expression in endothelial cells.10Pastore L Tessitore A Martinotti S Toniato E Alesse E Bravi M Ferri C Desideri M Gulino A Antucci A Angiotensin II stimulates ICAM-1 expression by human vascular endothelial cells and increases soluble ICAM-1 release in vivo.Circulation. 1999; 100: 1646-1652Crossref PubMed Scopus (221) Google Scholar, 11Tummala P Chen X-L Sundell C Laursen J Hammes C Alexander W Harrison D Medford R Angiotensin II induces vascular cell adhesion molecule-1 expression in rat vasculature: A potenial link between the renin angiotensin system and atherosclerosis.Circulation. 1999; 100: 1223-1229Crossref PubMed Scopus (327) Google Scholar Our unpublished observations support this finding and suggest that AT1A receptors promote adhesion of mouse leukocytes to endothelial cells. Alternatively, as demonstrated by Hisada et al,12Hisada Y Sugaya T Yamanouchi M Uchida H Fujimura H Sakurai H Fukamizu A Murakami K Angiotensin II plays a pathogenic role in immune-mediated renal injury in mice.J Clin Invest. 1999; 103: 627-635Crossref PubMed Scopus (133) Google Scholar angiotensin II may stimulate chemotaxis and leukocyte adhesion indirectly, by inducing production of chemokines such as monocyte chemoattractant protein-1 (MCP-1). Although our studies focused on a potential role for angiotensin II in alloimmunity and in applications related to transplantation, it is plausible that the proinflammatory actions of the RAS may contribute to the pathogenesis of other cardiovascular disorders. For example, inflammation is recognized as a critical element in the development of atherosclerosis.13Ross R Atherosclerosis is an inflammatory disease.Am Heart J. 1999; 138 (part 2): S419-S420Abstract Full Text Full Text PDF PubMed Google Scholar Studies in mice have documented the efficacy of AT1 receptor blockers to retard atherogenesis.14Hayek T Attias J Coleman R Brodsky S Smith J Breslow J Keidar S The angiotensin-converting enzyme inhibitor, fosinopril, and the angiotensin II receptor antagonist, losartan, inhibit LDL oxidation and attenuate atherosclerosis independent of lowering blood pressure in apolipoprotein E deficient mice.Cardiovasc Res. 1999; 44: 579-587Crossref PubMed Scopus (145) Google Scholar, 15Keider S Attias J Smith J Breslow J Hayek T The angiotensin II receptor antagonist losartan inhibits LDL peroxidation and atherosclerosis in apolipoprotein E-deficient mice.Biochem Biophys Res Commun. 1997; 236: 622-625Crossref PubMed Scopus (128) Google Scholar These actions may explain some of the clinical efficacy of ACE inhibitors to prevent cardiovascular morbidity and mortality.16Francis G ACE inhibition in cardiovascular disease.N Engl J Med. 2000; 342: 201-202Crossref PubMed Scopus (80) Google Scholar We suggest that the actions of angiotensin II to promote inflammatory cell migration and activation may contribute to the pathogenesis of these pervasive vascular diseases. Moreover, gene targeting approaches may be useful in defining the discrete contributions of vascular versus immunologic effects of angiotensin II in these processes. As Dr Morrissey points out, we did not directly examine AT1B receptor mRNA expression in the splenocyte system that we used in our experiments. However, several lines of evidence suggest that AT1B receptors play little or no role in promoting lymphocyte proliferation. First, specific angiotensin receptors were easily detected on lymphocytes from wild-type animals, and most of these sites conformed to the pharmacologic profile of AT1 receptors. In contrast, no significant angiotensin II binding could be detected on lymphocytes from AT1A− /− mice, suggesting that AT1A receptors are the only angiotensin receptors that were expressed on these cells; we found no evidence for residual binding to AT1B receptors on splenocytes from AT1A− /− mice. In a mixed lymphocyte reaction (MLR) that used wild-type cells, losartan, an antagonist of both AT1A and AT1B receptors, reduced proliferation to levels that were similar to those observed in MLR with AT1A− /− responders. Furthermore, losartan caused no further inhibition of proliferative responses in AT1A− /− cells. Our conclusion from these data is that the AT1B receptor does not play a role in regulating lymphocyte function and that virtually all of the effects of angiotensin II to modulate lymphocyte proliferation are mediated by AT1A receptors. We would finally like to amplify one additional point that was made by Dr Morrissey regarding the possibility that multiple second messengers and transcription factors that may mediate the immunologic actions of angiotensin II. In our discussion, we emphasized the role of the calcineurin-nuclear factor of activated T cells (NFAT) pathway because of its well-characterized and dominant actions in transplant rejection.17Schreiber S Crabtree G The mechanism of action of cyclosporin A and FK506.Immunol Today. 1992; 13: 136-142Abstract Full Text PDF PubMed Scopus (1947) Google Scholar In addition, studies from Eric Olsen’s laboratory had recently established a connection between angiotensin II and the calcineurin-NFAT system in nonimmune cells.18Molkentin J Lu J-R Antos C Markham B Richardson J Robbins J Grant S Olson E A calcineurin-dependent transcriptional pathway for cardiac hypertrophy.Cell. 1998; 93: 215-228Abstract Full Text Full Text PDF PubMed Scopus (2191) Google Scholar We agree with Dr Morrissey that other second messengers and transcription factors also may be involved. The NF-kB system is one prime candidate, and the JAK/STAT kinase system19Marrero M Schieffer B Paxton W Heerdt L Berk B Delafontaine P Bernstein K Direct stimulation of Jak/STAT pathway by the angiotensin II AT1 receptor.Nature. 1995; 375: 247-250Crossref PubMed Scopus (649) Google Scholar is another. We believe that identification of the molecular signaling pathways that mediate the proinflammatory actions of angiotensin II will be a promising future area for investigation. What are the practical applications of our findings? Historically, transplant physicians have not been enthusiastic about using ACE inhibitors or AT1 receptor blockers in organ allograft recipients. The reasons for this lack of enthusiasm probably include the perception that these patients tend to have a volume-expanded, “low renin” form of hypertension and that ACE inhibitors may have detrimental effects on renal function in patients treated with calcineurin antagonists or in the presence of transplant artery stenosis. However, we believe that these agents may have unique beneficial actions in the transplant patient. For example, there is a disproportionately high burden of cardiovascular disease among transplant patients, and the positive influence of ACE inhibition on cardiovascular morbidity and mortality is now well established.16Francis G ACE inhibition in cardiovascular disease.N Engl J Med. 2000; 342: 201-202Crossref PubMed Scopus (80) Google Scholar Furthermore, there is compelling evidence in preclinical models that ACE inhibitors and AT1 receptor blockers prevent chronic nephropathy caused by calcineurin antagonists.20Burdmann E Andoh T Nast C Evan A Connors B Coffman T Lindsley J Bennett W Prevention of experimental cyclosporine-induced interstitial fibrosis by losartan and enalApril.Am J Physiol. 1995; 269: F-491-F499Google Scholar Our study shows that these agents also directly inhibit alloimmune responses. Finally, our data indicate that AT1 receptor antagonists may potentiate the immunosuppressive actions of calcineurin inhibitors. Combined treatment with angiotensin receptor blocker and calcineurin inhibitor may provide a strategy for reducing the dose of calcineurin inhibitor that is required to maintain adequate immunosuppression, thereby reducing the potential risk of long-term toxicity. Of course, the clinical relevance of these observations will need to be tested.