J Am Soc Nephrol 28(5): 1350-1361

Immunologic Effects of the Renin-Angiotensin System

Division of Nephrology, Department of Medicine, Durham Veterans Affairs and Duke University Medical Centers, Durham, North Carolina

^{Corresponding author.}

Correspondence: Dr. Steven D. Crowley, Division of Nephrology, Department of Medicine, Durham VA and Duke University Medical Centers, DUMC Box 103015, Durham, NC 27710. Email: ude.ekud@yelworc.d.nevets

Abstract

Inappropriate activation of the renin-angiotensin system (RAS) exacerbates renal and vascular injury. Accordingly, treatment with global RAS antagonists attenuates cardiovascular risk and slows the progression of proteinuric kidney disease. By reducing BP, RAS inhibitors limit secondary immune activation responding to hemodynamic injury in the target organ. However, RAS activation in hematopoietic cells has immunologic effects that diverge from those of RAS stimulation in the kidney and vasculature. In preclinical studies, activating type 1 angiotensin (AT₁) receptors in T lymphocytes and myeloid cells blunts the polarization of these cells toward proinflammatory phenotypes, protecting the kidney from hypertensive injury and fibrosis. These endogenous functions of immune AT₁ receptors temper the pathogenic actions of renal and vascular AT₁ receptors during hypertension. By counteracting the effects of AT₁ receptor stimulation in the target organ, exogenous administration of AT₂ receptor agonists or angiotensin 1–7 analogs may similarly limit inflammatory injury to the heart and kidney. Moreover, although angiotensin II is the classic effector molecule of the RAS, several RAS enzymes affect immune homeostasis independently of canonic angiotensin II generation. Thus, as reviewed here, multiple components of the RAS signaling cascade influence inflammatory cell phenotype and function with unpredictable and context-specific effects on innate and adaptive immunity.

Keywords: immunology, hypertension, renin angiotensin system

Abstract

The renin-angiotensin system (RAS) is a critical hormonal signaling cascade engaged in body fluid and BP homeostasis (Figure 1). Reductions in kidney perfusion stimulate the RAS with consequent renal sodium retention and intravascular volume expansion.¹–³ Inappropriate activation of the RAS therefore leads to hypertension and progression of kidney and cardiovascular disease. Accordingly, medicines that block the actions of the RAS are among the most effective classes of agents used to reduce BP and ameliorate diabetic and nondiabetic kidney disease.⁴–⁷ Although the classically recognized functions of the RAS to promote renal sodium retention and vasoconstriction are mediated through the binding of angiotensin II (Ang II) to type 1 angiotensin (AT₁) receptors,⁸,⁹ other peptides, enzymes, and receptors in this cascade have received increased scrutiny for their independent contributions to developmental biology, renal and vascular function, and immunity. The discovery that the production of RAS components in kidney parenchymal cells is regulated independently of RAS peptide levels in the circulation introduced a paradigm shift in our understanding of how the RAS contributes to the pathogenesis of hypertension.¹⁰ Tissue-specific regulation and functions of the RAS are similarly evident in other organs including those engaged in innate and adaptive immune responses. Indeed, cell lineages that constitute the immune system have the capacity to express RAS components,¹¹,¹² and the effects of the RAS peptides and enzymes on inflammatory responses are quite diverse. However, one recurring theme that emerges from the work of several laboratories including our own is that activating AT₁ receptors directly on hematopoietic cells may provide a feedback, immunosuppressive signal to temper or limit the pathogenic actions of inappropriate RAS activation in the kidney, vasculature, and nervous system. Below, we highlight several of the immunologic effects of the RAS.

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Figure 1.

The renin angiotensin system. The RAS is composed of multiple substrates and enzymes that can act in concert or separately to exert physiologic actions. The most well described function of the RAS is regulation of BP homeostasis. Angiotensinogen is converted to Ang I by renin in the circulation. Ang I is subsequently cleaved by ACE to produce Ang II, an effector molecule that increases vascular tone and promotes sodium reabsorption in the kidney by ligating the AT₁ receptor. Apart from these canonic functions, several components of the RAS modulate immune responses. (Pro)renin and ACE regulate hematopoietic cell differentiation. AT₁ receptor activation in immune cells versus the kidney exerts divergent effects on tissue inflammation. By degrading Ang II and/or by catalyzing the generation of Ang 1–7, ACE2 ameliorates inflammatory injury in the kidney and vasculature.

Acknowledgments

This work was supported by National Institutes of Health grants DK087893, {"type":"entrez-nucleotide","attrs":{"text":"HL128355","term_id":"1051906939","term_text":"HL128355"}}HL128355, and P30DK096493; Veterans Health Administration, Office of Research and Development, Biomedical Laboratory Research and Development Grant BX000893; and the Edna and Fred L. Mandel Center for Hypertension and Atherosclerosis Research.

Acknowledgments

Footnotes

Published online ahead of print. Publication date available at www.jasn.org.

Footnotes

References

1. Goldblatt H, Lynch J, Hanzal RF, Summerville WW.: Studies on experimental hypertension: I. The production of persistent elevation of systolic blood pressure by means of renal ischemia.J Exp Med59: 347–379, 1934
2. Guyton AC: Blood pressure control--special role of the kidneys and body fluids.Science252: 1813–1816, 1991 [[PubMed]
3. Hall JE, Brands MW, Henegar JR.: Angiotensin II and long-term arterial pressure regulation: The overriding dominance of the kidney.J Am Soc Nephrol10Suppl 12]: S258–S265, 1999 [[PubMed]
4. Taal MW, Brenner BM.: Renoprotective benefits of RAS inhibition: From ACEI to angiotensin II antagonists.Kidney Int57: 1803–1817, 2000 [[PubMed]
5. Lewis EJ, Hunsicker LG, Bain RP, Rohde RD; The Collaborative Study Group .: The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy.N Engl J Med329: 1456–1462, 1993 [[PubMed]
6. Maschio G, Alberti D, Janin G, Locatelli F, Mann JF, Motolese M, Ponticelli C, Ritz E, Zucchelli P; The Angiotensin-Converting-Enzyme Inhibition in Progressive Renal Insufficiency Study Group .: Effect of the angiotensin-converting-enzyme inhibitor benazepril on the progression of chronic renal insufficiency.N Engl J Med334: 939–945, 1996 [[PubMed]
7. Dahlöf B, Devereux RB, Kjeldsen SE, Julius S, Beevers G, de Faire U, Fyhrquist F, Ibsen H, Kristiansson K, Lederballe-Pedersen O, Lindholm LH, Nieminen MS, Omvik P, Oparil S, Wedel H; LIFE Study Group .: Cardiovascular morbidity and mortality in the Losartan Intervention for Endpoint reduction in hypertension study (LIFE): A randomised trial against atenolol.Lancet359: 995–1003, 2002 [[PubMed]
8. Ito M, Oliverio MI, Mannon PJ, Best CF, Maeda N, Smithies O, Coffman TM.: Regulation of blood pressure by the type 1A angiotensin II receptor gene.Proc Natl Acad Sci USA92: 3521–3525, 1995
9. Oliverio MI, Best CF, Smithies O, Coffman TM.: Regulation of sodium balance and blood pressure by the AT(1A) receptor for angiotensin II.Hypertension35: 550–554, 2000 [[PubMed]
10. Navar LG, Kobori H, Prieto MC, Gonzalez-Villalobos RA.: Intratubular renin-angiotensin system in hypertension.Hypertension57: 355–362, 2011
11. Nataraj C, Oliverio MI, Mannon RB, Mannon PJ, Audoly LP, Amuchastegui CS, Ruiz P, Smithies O, Coffman TM.: Angiotensin II regulates cellular immune responses through a calcineurin-dependent pathway.J Clin Invest104: 1693–1701, 1999
12. Jurewicz M, McDermott DH, Sechler JM, Tinckam K, Takakura A, Carpenter CB, Milford E, Abdi R.: Human T and natural killer cells possess a functional renin-angiotensin system: Further mechanisms of angiotensin II-induced inflammation.J Am Soc Nephrol18: 1093–1102, 2007 [[PubMed]
13. Ruiz-Ortega M, Ruperez M, Lorenzo O, Esteban V, Blanco J, Mezzano S, Egido J.: Angiotensin II regulates the synthesis of proinflammatory cytokines and chemokines in the kidney.Kidney Int62Suppl 82]: S12–S22, 2002 [[PubMed]
14. Ruiz-Ortega M, Bustos C, Hernández-Presa MA, Lorenzo O, Plaza JJ, Egido J.: Angiotensin II participates in mononuclear cell recruitment in experimental immune complex nephritis through nuclear factor-kappa B activation and monocyte chemoattractant protein-1 synthesis.J Immunol161: 430–439, 1998 [[PubMed]
15. Guo S, Kowalewska J, Wietecha TA, Iyoda M, Wang L, Yi K, Spencer M, Banas M, Alexandrescu S, Hudkins KL, Alpers CE.: Renin-angiotensin system blockade is renoprotective in immune complex-mediated glomerulonephritis.J Am Soc Nephrol19: 1168–1176, 2008
16. Pérez De Lema G, De Wit C, Cohen CD, Nieto E, Molina A, Banas B, Luckow B, Vicente AB, Mampaso F, Schlöndorff D.: Angiotensin inhibition reduces glomerular damage and renal chemokine expression in MRL/lpr mice.J Pharmacol Exp Ther307: 275–281, 2003 [[PubMed]
17. Hernández-Presa M, Bustos C, Ortego M, Tuñon J, Renedo G, Ruiz-Ortega M, Egido J.: Angiotensin-converting enzyme inhibition prevents arterial nuclear factor-kappa B activation, monocyte chemoattractant protein-1 expression, and macrophage infiltration in a rabbit model of early accelerated atherosclerosis.Circulation95: 1532–1541, 1997 [[PubMed]
18. Border WA, Noble NA.: Interactions of transforming growth factor-beta and angiotensin II in renal fibrosis.Hypertension31: 181–188, 1998 [[PubMed]
19. Wolf G, Mueller E, Stahl RA, Ziyadeh FN.: Angiotensin II-induced hypertrophy of cultured murine proximal tubular cells is mediated by endogenous transforming growth factor-beta.J Clin Invest92: 1366–1372, 1993
20. Lanz TV, Ding Z, Ho PP, Luo J, Agrawal AN, Srinagesh H, Axtell R, Zhang H, Platten M, Wyss-Coray T, Steinman L.: Angiotensin II sustains brain inflammation in mice via TGF-beta.J Clin Invest120: 2782–2794, 2010
21. Agarwal R: Proinflammatory effects of oxidative stress in chronic kidney disease: Role of additional angiotensin II blockade.Am J Physiol Renal Physiol284: F863–F869, 2003 [[PubMed]
22. Sparks MA, Stegbauer J, Chen D, Gomez JA, Griffiths RC, Azad HA, Herrera M, Gurley SB, Coffman TM.: Vascular type 1A angiotensin II receptors control BP by regulating renal blood flow and urinary sodium excretion.J Am Soc Nephrol26: 2953–2962, 2015
23. Crowley SD, Gurley SB, Herrera MJ, Ruiz P, Griffiths R, Kumar AP, Kim HS, Smithies O, Le TH, Coffman TM.: Angiotensin II causes hypertension and cardiac hypertrophy through its receptors in the kidney.Proc Natl Acad Sci USA103: 17985–17990, 2006
24. Muller DN, Shagdarsuren E, Park JK, Dechend R, Mervaala E, Hampich F, Fiebeler A, Ju X, Finckenberg P, Theuer J, Viedt C, Kreuzer J, Heidecke H, Haller H, Zenke M, Luft FC.: Immunosuppressive treatment protects against angiotensin II-induced renal damage.Am J Pathol161: 1679–1693, 2002
25. Guzik TJ, Hoch NE, Brown KA, McCann LA, Rahman A, Dikalov S, Goronzy J, Weyand C, Harrison DG.: Role of the T cell in the genesis of angiotensin II induced hypertension and vascular dysfunction.J Exp Med204: 2449–2460, 2007
26. Crowley SD, Song YS, Lin EE, Griffiths R, Kim HS, Ruiz P.: Lymphocyte responses exacerbate angiotensin II-dependent hypertension.Am J Physiol Regul Integr Comp Physiol298: R1089–R1097, 2010
27. Franco M, Tapia E, Santamaría J, Zafra I, García-Torres R, Gordon KL, Pons H, Rodríguez-Iturbe B, Johnson RJ, Herrera-Acosta J.: Renal cortical vasoconstriction contributes to development of salt-sensitive hypertension after angiotensin II exposure.J Am Soc Nephrol12: 2263–2271, 2001 [[PubMed]
28. Kleinewietfeld M, Manzel A, Titze J, Kvakan H, Yosef N, Linker RA, Muller DN, Hafler DA.: Sodium chloride drives autoimmune disease by the induction of pathogenic TH17 cells.Nature496: 518–522, 2013
29. Shao J, Nangaku M, Miyata T, Inagi R, Yamada K, Kurokawa K, Fujita T.: Imbalance of T-cell subsets in angiotensin II-infused hypertensive rats with kidney injury.Hypertension42: 31–38, 2003 [[PubMed]
30. Ozawa Y, Kobori H, Suzaki Y, Navar LG.: Sustained renal interstitial macrophage infiltration following chronic angiotensin II infusions.Am J Physiol Renal Physiol292: F330–F339, 2007
31. Hisada Y, Sugaya T, Tanaka S, Suzuki Y, Ra C, Kimura K, Fukamizu A.: An essential role of angiotensin II receptor type 1a in recipient kidney, not in transplanted peripheral blood leukocytes, in progressive immune-mediated renal injury.Lab Invest81: 1243–1251, 2001 [[PubMed]
32. Hisada 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 Invest103: 627–635, 1999
33. Crowley SD, Vasievich MP, Ruiz P, Gould SK, Parsons KK, Pazmino AK, Facemire C, Chen BJ, Kim HS, Tran TT, Pisetsky DS, Barisoni L, Prieto-Carrasquero MC, Jeansson M, Foster MH, Coffman TM.: Glomerular type 1 angiotensin receptors augment kidney injury and inflammation in murine autoimmune nephritis.J Clin Invest119: 943–953, 2009
34. Lu H, Rateri DL, Feldman DL, Charnigo RJ Jr, Fukamizu A, Ishida J, Oesterling EG, Cassis LA, Daugherty A.: Renin inhibition reduces hypercholesterolemia-induced atherosclerosis in mice.J Clin Invest118: 984–993, 2008
35. Koga J, Egashira K, Matoba T, Kubo M, Ihara Y, Iwai M, Horiuchi M, Sunagawa K.: Essential role of angiotensin II type 1a receptors in the host vascular wall, but not the bone marrow, in the pathogenesis of angiotensin II-induced atherosclerosis.Hypertens Res31: 1791–1800, 2008 [[PubMed]
36. Henke N, Schmidt-Ullrich R, Dechend R, Park JK, Qadri F, Wellner M, Obst M, Gross V, Dietz R, Luft FC, Scheidereit C, Muller DN.: Vascular endothelial cell-specific NF-kappaB suppression attenuates hypertension-induced renal damage.Circ Res101: 268–276, 2007 [[PubMed]
37. Nguyen G, Delarue F, Burcklé C, Bouzhir L, Giller T, Sraer JD.: Pivotal role of the renin/prorenin receptor in angiotensin II production and cellular responses to renin.J Clin Invest109: 1417–1427, 2002
38. Cruciat CM, Ohkawara B, Acebron SP, Karaulanov E, Reinhard C, Ingelfinger D, Boutros M, Niehrs C.: Requirement of prorenin receptor and vacuolar H+-ATPase-mediated acidification for Wnt signaling.Science327: 459–463, 2010 [[PubMed]
39. Shi P, Grobe JL, Desland FA, Zhou G, Shen XZ, Shan Z, Liu M, Raizada MK, Sumners C.: Direct pro-inflammatory effects of prorenin on microglia.PLoS One9: e92937, 2014
40. Satofuka S, Ichihara A, Nagai N, Noda K, Ozawa Y, Fukamizu A, Tsubota K, Itoh H, Oike Y, Ishida S.: (Pro)renin receptor-mediated signal transduction and tissue renin-angiotensin system contribute to diabetes-induced retinal inflammation.Diabetes58: 1625–1633, 2009
41. Feldt S, Batenburg WW, Mazak I, Maschke U, Wellner M, Kvakan H, Dechend R, Fiebeler A, Burckle C, Contrepas A, Jan Danser AH, Bader M, Nguyen G, Luft FC, Muller DN.: Prorenin and renin-induced extracellular signal-regulated kinase 1/2 activation in monocytes is not blocked by aliskiren or the handle-region peptide.Hypertension51: 682–688, 2008 [[PubMed]
42. Geisberger S, Maschke U, Gebhardt M, Kleinewietfeld M, Manzel A, Linker RA, Chidgey A, Dechend R, Nguyen G, Daumke O, Muller DN, Wright MD, Binger KJ.: New role for the (pro)renin receptor in T-cell development.Blood126: 504–507, 2015 [[PubMed]
43. Narumi K, Hirose T, Sato E, Mori T, Kisu K, Ishikawa M, Totsune K, Ishii T, Ichihara A, Nguyen G, Sato H, Ito S.: A functional (pro)renin receptor is expressed in human lymphocytes and monocytes.Am J Physiol Renal Physiol308: F487–F499, 2015 [[PubMed]
44. Pfeffer MA, Braunwald E, Moyé LA, Basta L, Brown EJ Jr, Cuddy TE, Davis BR, Geltman EM, Goldman S, Flaker GC, Klein M, Lamas GA, Packer M, Rouleau J, Rouleau JL, Rutherford J, Wertheimer JH, Morton Hawkins C; The SAVE Investigators .: Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. Results of the survival and ventricular enlargement trial.N Engl J Med327: 669–677, 1992 [[PubMed]
45. Schieffer B, Bünte C, Witte J, Hoeper K, Böger RH, Schwedhelm E, Drexler H.: Comparative effects of AT1-antagonism and angiotensin-converting enzyme inhibition on markers of inflammation and platelet aggregation in patients with coronary artery disease.J Am Coll Cardiol44: 362–368, 2004 [[PubMed]
46. Brull DJ, Sanders J, Rumley A, Lowe GD, Humphries SE, Montgomery HE.: Impact of angiotensin converting enzyme inhibition on post-coronary artery bypass interleukin 6 release.Heart87: 252–255, 2002
47. Nakamura T, Sato E, Fujiwara N, Kawagoe Y, Yamada S, Ueda Y, Koide H.: Changes in urinary albumin excretion, inflammatory and oxidative stress markers in ADPKD patients with hypertension.Am J Med Sci343: 46–51, 2012 [[PubMed]
48. Mandelia A, Bajpai M, Agarwala S, Gupta AK, Kumar R, Ali A.: The role of urinary TGF-β₁, TNF-α, IL-6 and microalbuminuria for monitoring therapy in posterior urethral valves.Pediatr Nephrol28: 1991–2001, 2013 [[PubMed]
49. Lieberman J: Elevation of serum angiotensin-converting-enzyme (ACE) level in sarcoidosis.Am J Med59: 365–372, 1975 [[PubMed]
50. Weinstock JV, Ehrinpreis MN, Boros DL, Gee JB.: Effect of SQ 14225, an inhibitor of angiotensin I-converting enzyme, on the granulomatous response to Schistosoma mansoni eggs in mice.J Clin Invest67: 931–936, 1981
51. Zambidis ET, Park TS, Yu W, Tam A, Levine M, Yuan X, Pryzhkova M, Péault B.: Expression of angiotensin-converting enzyme (CD143) identifies and regulates primitive hemangioblasts derived from human pluripotent stem cells.Blood112: 3601–3614, 2008
52. Gossmann J, Thürmann P, Bachmann T, Weller S, Kachel HG, Schoeppe W, Scheuermann EH.: Mechanism of angiotensin converting enzyme inhibitor-related anemia in renal transplant recipients.Kidney Int50: 973–978, 1996 [[PubMed]
53. Shen XZ, Billet S, Lin C, Okwan-Duodu D, Chen X, Lukacher AE, Bernstein KE.: The carboxypeptidase ACE shapes the MHC class I peptide repertoire.Nat Immunol12: 1078–1085, 2011
54. Thomas MC, Pickering RJ, Tsorotes D, Koitka A, Sheehy K, Bernardi S, Toffoli B, Nguyen-Huu TP, Head GA, Fu Y, Chin-Dusting J, Cooper ME, Tikellis C.: Genetic Ace2 deficiency accentuates vascular inflammation and atherosclerosis in the ApoE knockout mouse.Circ Res107: 888–897, 2010 [[PubMed]
55. Liu Z, Huang XR, Chen HY, Penninger JM, Lan HY.: Loss of angiotensin-converting enzyme 2 enhances TGF-β/Smad-mediated renal fibrosis and NF-κB-driven renal inflammation in a mouse model of obstructive nephropathy.Lab Invest92: 650–661, 2012 [[PubMed]
56. Al-Maghrebi M, Benter IF, Diz DI.: Endogenous angiotensin-(1-7) reduces cardiac ischemia-induced dysfunction in diabetic hypertensive rats.Pharmacol Res59: 263–268, 2009
57. Zhang J, Noble NA, Border WA, Huang Y.: Infusion of angiotensin-(1-7) reduces glomerulosclerosis through counteracting angiotensin II in experimental glomerulonephritis.Am J Physiol Renal Physiol298: F579–F588, 2010
58. da Silveira KD, Coelho FM, Vieira AT, Sachs D, Barroso LC, Costa VV, Bretas TL, Bader M, de Sousa LP, da Silva TA, dos Santos RA, Simões e Silva AC, Teixeira MM.: Anti-inflammatory effects of the activation of the angiotensin-(1-7) receptor, MAS, in experimental models of arthritis.J Immunol185: 5569–5576, 2010 [[PubMed]
59. Esteban V, Heringer-Walther S, Sterner-Kock A, de Bruin R, van den Engel S, Wang Y, Mezzano S, Egido J, Schultheiss HP, Ruiz-Ortega M, Walther T.: Angiotensin-(1-7) and the g protein-coupled receptor MAS are key players in renal inflammation.PLoS One4: e5406, 2009
60. Crowley SD, Song YS, Sprung G, Griffiths R, Sparks M, Yan M, Burchette JL, Howell DN, Lin EE, Okeiyi B, Stegbauer J, Yang Y, Tharaux PL, Ruiz P.: A role for angiotensin II type 1 receptors on bone marrow-derived cells in the pathogenesis of angiotensin II-dependent hypertension.Hypertension55: 99–108, 2010
61. Hoch NE, Guzik TJ, Chen W, Deans T, Maalouf SA, Gratze P, Weyand C, Harrison DG.: Regulation of T-cell function by endogenously produced angiotensin II.Am J Physiol Regul Integr Comp Physiol296: R208–R216, 2009
62. Kato H, Ishida J, Nagano K, Honjo K, Sugaya T, Takeda N, Sugiyama F, Yagami K, Fujita T, Nangaku M, Fukamizu A.: Deterioration of atherosclerosis in mice lacking angiotensin II type 1A receptor in bone marrow-derived cells.Lab Invest88: 731–739, 2008 [[PubMed]
63. Zhang JD, Patel MB, Griffiths R, Dolber PC, Ruiz P, Sparks MA, Stegbauer J, Jin H, Gomez JA, Buckley AF, Lefler WS, Chen D, Crowley SD.: Type 1 angiotensin receptors on macrophages ameliorate IL-1 receptor-mediated kidney fibrosis.J Clin Invest124: 2198–2203, 2014
64. Zhang JD, Patel MB, Song YS, Griffiths R, Burchette J, Ruiz P, Sparks MA, Yan M, Howell DN, Gomez JA, Spurney RF, Coffman TM, Crowley SD.: A novel role for type 1 angiotensin receptors on T lymphocytes to limit target organ damage in hypertension.Circ Res110: 1604–1617, 2012
65. Zhang J, Patel MB, Griffiths R, Mao A, Song YS, Karlovich NS, Sparks MA, Jin H, Wu M, Lin EE, Crowley SD.: Tumor necrosis factor-α produced in the kidney contributes to angiotensin II-dependent hypertension.Hypertension64: 1275–1281, 2014
66. Nishida M, Fujinaka H, Matsusaka T, Price J, Kon V, Fogo AB, Davidson JM, Linton MF, Fazio S, Homma T, Yoshida H, Ichikawa I.: Absence of angiotensin II type 1 receptor in bone marrow-derived cells is detrimental in the evolution of renal fibrosis.J Clin Invest110: 1859–1868, 2002
67. Ma LJ, Corsa BA, Zhou J, Yang H, Li H, Tang YW, Babaev VR, Major AS, Linton MF, Fazio S, Hunley TE, Kon V, Fogo AB.: Angiotensin type 1 receptor modulates macrophage polarization and renal injury in obesity.Am J Physiol Renal Physiol300: F1203–F1213, 2011
68. Siragy HM: The angiotensin II type 2 receptor and the kidney.J Renin Angiotensin Aldosterone Syst11: 33–36, 2010
69. Arendshorst WJ, Brännström K, Ruan X.: Actions of angiotensin II on the renal microvasculature.J Am Soc Nephrol10Suppl 11]: S149–S161, 1999 [[PubMed]
70. Curato C, Slavic S, Dong J, Skorska A, Altarche-Xifró W, Miteva K, Kaschina E, Thiel A, Imboden H, Wang J, Steckelings U, Steinhoff G, Unger T, Li J.: Identification of noncytotoxic and IL-10-producing CD8+AT2R+ T cell population in response to ischemic heart injury.J Immunol185: 6286–6293, 2010 [[PubMed]
71. Skorska A, von Haehling S, Ludwig M, Lux CA, Gaebel R, Kleiner G, Klopsch C, Dong J, Curato C, Altarche-Xifró W, Slavic S, Unger T, Steinhoff G, Li J, David R.: The CD4(+) AT2R(+) T cell subpopulation improves post-infarction remodelling and restores cardiac function.J Cell Mol Med19: 1975–1985, 2015
72. Wan Y, Wallinder C, Plouffe B, Beaudry H, Mahalingam AK, Wu X, Johansson B, Holm M, Botoros M, Karlén A, Pettersson A, Nyberg F, Fändriks L, Gallo-Payet N, Hallberg A, Alterman M.: Design, synthesis, and biological evaluation of the first selective nonpeptide AT2 receptor agonist.J Med Chem47: 5995–6008, 2004 [[PubMed]
73. Kaschina E, Grzesiak A, Li J, Foryst-Ludwig A, Timm M, Rompe F, Sommerfeld M, Kemnitz UR, Curato C, Namsolleck P, Tschöpe C, Hallberg A, Alterman M, Hucko T, Paetsch I, Dietrich T, Schnackenburg B, Graf K, Dahlöf B, Kintscher U, Unger T, Steckelings UM.: Angiotensin II type 2 receptor stimulation: A novel option of therapeutic interference with the renin-angiotensin system in myocardial infarction?Circulation118: 2523–2532, 2008 [[PubMed]
74. Sabuhi R, Ali Q, Asghar M, Al-Zamily NR, Hussain T.: Role of the angiotensin II AT2 receptor in inflammation and oxidative stress: Opposing effects in lean and obese Zucker rats.Am J Physiol Renal Physiol300: F700–F706, 2011
75. Dhande I, Ali Q, Hussain T.: Proximal tubule angiotensin AT2 receptors mediate an anti-inflammatory response via interleukin-10: Role in renoprotection in obese rats.Hypertension61: 1218–1226, 2013
76. Rompe F, Artuc M, Hallberg A, Alterman M, Ströder K, Thöne-Reineke C, Reichenbach A, Schacherl J, Dahlöf B, Bader M, Alenina N, Schwaninger M, Zuberbier T, Funke-Kaiser H, Schmidt C, Schunck WH, Unger T, Steckelings UM.: Direct angiotensin II type 2 receptor stimulation acts anti-inflammatory through epoxyeicosatrienoic acid and inhibition of nuclear factor kappaB.Hypertension55: 924–931, 2010 [[PubMed]
77. Cherney DZ, Reich HN, Scholey JW, Daneman D, Mahmud FH, Har RL, Sochett EB.: The effect of aliskiren on urinary cytokine/chemokine responses to clamped hyperglycaemia in type 1 diabetes.Diabetologia56: 2308–2317, 2013 [[PubMed]
78. Morishita Y, Hanawa S, Chinda J, Iimura O, Tsunematsu S, Kusano E.: Effects of aliskiren on blood pressure and the predictive biomarkers for cardiovascular disease in hemodialysis-dependent chronic kidney disease patients with hypertension.Hypertens Res34: 308–313, 2011 [[PubMed]
79. Parving HH, Brenner BM, McMurray JJ, de Zeeuw D, Haffner SM, Solomon SD, Chaturvedi N, Persson F, Desai AS, Nicolaides M, Richard A, Xiang Z, Brunel P, Pfeffer MA; ALTITUDE Investigators .: Cardiorenal end points in a trial of aliskiren for type 2 diabetes.N Engl J Med367: 2204–2213, 2012 [[PubMed]
80. Brenner BM, Cooper ME, de Zeeuw D, Keane WF, Mitch WE, Parving HH, Remuzzi G, Snapinn SM, Zhang Z, Shahinfar S; RENAAL Study Investigators .: Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy.N Engl J Med345: 861–869, 2001 [[PubMed]
81. Itani HA, McMaster WG Jr, Saleh MA, Nazarewicz RR, Mikolajczyk TP, Kaszuba AM, Konior A, Prejbisz A, Januszewicz A, Norlander AE, Chen W, Bonami RH, Marshall AF, Poffenberger G, Weyand CM, Madhur MS, Moore DJ, Harrison DG, Guzik TJ.: Activation of human T cells in hypertension: Studies of humanized mice and hypertensive humans.Hypertension68: 123–132, 2016
82. Di Paolo S, Schena A, Stallone G, Grandaliano G, Soccio M, Cerullo G, Gesualdo L, Paolo Schena F.: Captopril enhances transforming growth factor (TGF)-beta1 expression in peripheral blood mononuclear cells: A mechanism independent from angiotensin converting enzyme inhibition? A study in cyclosporine-treated kidney-transplanted patients.Transplantation74: 1710–1715, 2002 [[PubMed]
83. Koh KK, Ahn JY, Han SH, Kim DS, Jin DK, Kim HS, Shin MS, Ahn TH, Choi IS, Shin EK.: Pleiotropic effects of angiotensin II receptor blocker in hypertensive patients.J Am Coll Cardiol42: 905–910, 2003 [[PubMed]
84. Sonmez A, Kisa U, Uckaya G, Eyileten T, Comert B, Koc B, Kocabalkan F, Ozata M.: Effects of losartan treatment on T-cell activities and plasma leptin concentrations in primary hypertension.J Renin Angiotensin Aldosterone Syst2: 112–116, 2001 [[PubMed]
85. Koh KK, Quon MJ, Han SH, Chung WJ, Ahn JY, Seo YH, Kang MH, Ahn TH, Choi IS, Shin EK.: Additive beneficial effects of losartan combined with simvastatin in the treatment of hypercholesterolemic, hypertensive patients.Circulation110: 3687–3692, 2004 [[PubMed]
86. Lopez Santi RG, Valeff EC, Duymovich CR, Mazziotta D, Mijailovsky NE, Filippa GC, Maltez R, Hernandez VA, Monroy AG, Borzi JG, Acheme RA, Etchegoyen MC; PROCORDIS investigators .: Effects of an angiotensin-converting enzyme inhibitor (ramipril) on inflammatory markers in secondary prevention patients: RAICES Study.Coron Artery Dis16: 423–429, 2005 [[PubMed]
87. Di Napoli M, Papa F.: Angiotensin-converting enzyme inhibitor use is associated with reduced plasma concentration of C-reactive protein in patients with first-ever ischemic stroke.Stroke34: 2922–2929, 2003 [[PubMed]
88. Tsuruoka S, Kai H, Usui J, Morito N, Saito C, Yoh K, Yamagata K.: Effects of irbesartan on inflammatory cytokine concentrations in patients with chronic glomerulonephritis.Intern Med52: 303–308, 2013 [[PubMed]
89. Kintscher U, Marx N, Martus P, Stoppelhaar M, Schimkus J, Schneider A, Walcher D, Kümmel A, Winkler R, Kappert K, Dörffel Y, Scholze J, Unger T.: Effect of high-dose valsartan on inflammatory and lipid parameters in patients with Type 2 diabetes and hypertension.Diabetes Res Clin Pract89: 209–215, 2010 [[PubMed]
90. Gamboa JL, Pretorius M, Todd-Tzanetos DR, Luther JM, Yu C, Ikizler TA, Brown NJ.: Comparative effects of angiotensin-converting enzyme inhibition and angiotensin-receptor blockade on inflammation during hemodialysis.J Am Soc Nephrol23: 334–342, 2012
91. Sato H, Akai Y, Iwano M, Kurumatani N, Kurioka H, Kubo A, Yamaguchi T, Fujimoto T, Dohi K.: Association of an insertion polymorphism of angiotensin-converting enzyme gene with the activity of systemic lupus erythematosus.Lupus7: 530–534, 1998 [[PubMed]
92. Akai Y, Sato H, Iwano M, Kurumatani N, Kurioka H, Kubo A, Yamaguchi T, Shiiki H, Fujimoto T, Dohi K.: Association of an insertion polymorphism of angiotensin-converting enzyme gene with the activity of lupus nephritis.Clin Nephrol51: 141–146, 1999 [[PubMed]
93. Tavana S, Argani H, Gholamin S, Razavi SM, Keshtkar-Jahromi M, Talebian AS, Moghaddam KG, Sepehri Z, Azad TM, Keshtkar-Jahromi M.: Influenza vaccination in patients with pulmonary sarcoidosis: Efficacy and safety.Influenza Other Respi Viruses6: 136–141, 2012
94. Prkacin I, Novak B, Sertić J, Mrzljak A.: Angiotensin-converting enzyme gene polymorphism in patients with systemic lupus.Acta Med Croatica55: 73–76, 2001 [[PubMed]
95. Kaufman KM, Kelly J, Gray-McGuire C, Asundi N, Yu H, Reid J, Baird T, Hutchings D, Bruner G, Scofield RH, Moser K, Harley JB.: Linkage analysis of angiotensin-converting enzyme (ACE) insertion/deletion polymorphism and systemic lupus erythematosus.Mol Cell Endocrinol177: 81–85, 2001 [[PubMed]
96. Rubio-Tapia A, Herman ML, Ludvigsson JF, Kelly DG, Mangan TF, Wu TT, Murray JA.: Severe spruelike enteropathy associated with olmesartan.Mayo Clin Proc87: 732–738, 2012
97. Ianiro G, Bibbò S, Montalto M, Ricci R, Gasbarrini A, Cammarota G.: Systematic review: Sprue-like enteropathy associated with olmesartan.Aliment Pharmacol Ther40: 16–23, 2014 [[PubMed]
98. Marthey L, Cadiot G, Seksik P, Pouderoux P, Lacroute J, Skinazi F, Mesnard B, Chayvialle JA, Savoye G, Druez A, Parlier D, Abitbol V, Gompel M, Eoche M, Poncin E, Bobichon R, Colardelle P, Wils P, Salloum H, Peschard S, Zerbib F, Méresse B, Cerf-Bensussan N, Malamut G, Carbonnel F.: Olmesartan-associated enteropathy: Results of a national survey.Aliment Pharmacol Ther40: 1103–1109, 2014 [[PubMed]
99. Yusuf S, Teo KK, Pogue J, Dyal L, Copland I, Schumacher H, Dagenais G, Sleight P, Anderson C; ONTARGET Investigators .: Telmisartan, ramipril, or both in patients at high risk for vascular events.N Engl J Med358: 1547–1559, 2008 [[PubMed]
100. Fried LF, Emanuele N, Zhang JH, Brophy M, Conner TA, Duckworth W, Leehey DJ, McCullough PA, O’Connor T, Palevsky PM, Reilly RF, Seliger SL, Warren SR, Watnick S, Peduzzi P, Guarino P; VA NEPHRON-D Investigators .: Combined angiotensin inhibition for the treatment of diabetic nephropathy.N Engl J Med369: 1892–1903, 2013 [[PubMed]
101. Titan SM, M Vieira J Jr, Dominguez WV, Barros RT, Zatz R.: ACEI and ARB combination therapy in patients with macroalbuminuric diabetic nephropathy and low socioeconomic level: A double-blind randomized clinical trial.Clin Nephrol76: 273–283, 2011 [[PubMed]
102. Neri Serneri GG, Boddi M, Modesti PA, Coppo M, Cecioni I, Toscano T, Papa ML, Bandinelli M, Lisi GF, Chiavarelli M.: Cardiac angiotensin II participates in coronary microvessel inflammation of unstable angina and strengthens the immunomediated component.Circ Res94: 1630–1637, 2004 [[PubMed]
103. Tsikouris JP, Suarez JA, Simoni JS, Ziska M, Meyerrose GE.: Exploring the effects of ACE inhibitor tissue penetration on vascular inflammation following acute myocardial infarction.Coron Artery Dis15: 211–217, 2004 [[PubMed]
104. Ayoub MA, Zhang Y, Kelly RS, See HB, Johnstone EK, McCall EA, Williams JH, Kelly DJ, Pfleger KD.: Functional interaction between angiotensin II receptor type 1 and chemokine (C-C motif) receptor 2 with implications for chronic kidney disease.PLoS One10: e0119803, 2015
105. Herrera J, Ferrebuz A, MacGregor EG, Rodriguez-Iturbe B.: Mycophenolate mofetil treatment improves hypertension in patients with psoriasis and rheumatoid arthritis.J Am Soc Nephrol17Suppl 3]: S218–S225, 2006 [[PubMed]
106. Yoshida S, Takeuchi T, Kotani T, Yamamoto N, Hata K, Nagai K, Shoda T, Takai S, Makino S, Hanafusa T.: Infliximab, a TNF-α inhibitor, reduces 24-h ambulatory blood pressure in rheumatoid arthritis patients.J Hum Hypertens28: 165–169, 2014 [[PubMed]
107. Kobori H, Prieto-Carrasquero MC, Ozawa Y, Navar LG.: AT1 receptor mediated augmentation of intrarenal angiotensinogen in angiotensin II-dependent hypertension.Hypertension43: 1126–1132, 2004
108. Woodard LE, Wilson MH.: piggyBac-ing models and new therapeutic strategies.Trends Biotechnol33: 525–533, 2015
109. Miyagi A, Lu A, Humphreys BD.: Gene editing: Powerful new tools for nephrology research and therapy.J Am Soc Nephrol27: 2940–2947, 2016
110. Zhang J, Rudemiller NP, Patel MB, Wei Q, Karlovich NS, Jeffs AD, Wu M, Sparks MA, Privratsky JR, Herrera M, Gurley SB, Nedospasov SA, Crowley SD.: Competing actions of type 1 angiotensin II receptors expressed on T lymphocytes and kidney epithelium during cisplatin-induced AKI.J Am Soc Nephrol27: 2257–2264, 2016
111. Zhang J, Rudemiller NP, Patel MB, Karlovich NS, Wu M, McDonough AA, Griffiths R, Sparks MA, Jeffs AD, Crowley SD.: Interleukin-1 receptor activation potentiates salt reabsorption in angiotensin II-induced hypertension via the NKCC2 co-transporter in the nephron.Cell Metab23: 360–368, 2016
112. Nowak KL, Chonchol M, Ikizler TA, Farmer-Bailey H, Salas N, Chaudhry R, Wang W, Smits G, Tengesdal I, Dinarello CA, Hung AM.: IL-1 inhibition and vascular function in CKD [published online ahead of print September 19, 2016].J Am Soc Nephrol doi:10.1681/ASN.2016040453 ] [
113. Petty WJ, Miller AA, McCoy TP, Gallagher PE, Tallant EA, Torti FM.: Phase I and pharmacokinetic study of angiotensin-(1-7), an endogenous antiangiogenic hormone.Clin Cancer Res15: 7398–7404, 2009
114. Usher MG, Duan SZ, Ivaschenko CY, Frieler RA, Berger S, Schütz G, Lumeng CN, Mortensen RM.: Myeloid mineralocorticoid receptor controls macrophage polarization and cardiovascular hypertrophy and remodeling in mice.J Clin Invest120: 3350–3364, 2010