Immunologic Effects of the Renin-Angiotensin System
Total Page：16
File Type：pdf, Size：1020Kb
BRIEF REVIEW www.jasn.org Immunologic Effects of the Renin-Angiotensin System Steven D. Crowley and Nathan P. Rudemiller Division of Nephrology, Department of Medicine, Durham Veterans Affairs and Duke University Medical Centers, Durham, North Carolina ABSTRACT Inappropriate activation of the renin-angiotensin system (RAS) exacerbates renal cell lineages that constitute the immune and vascular injury. Accordingly, treatment with global RAS antagonists attenuates system have the capacity to express RAS cardiovascular risk and slows the progression of proteinuric kidney disease. By re- components,11,12 and the effects of the ducing BP, RAS inhibitors limit secondary immune activation responding to hemo- RAS peptides and enzymes on inflamma- dynamic injury in the target organ. However, RAS activation in hematopoietic cells tory responses are quite diverse. How- has immunologic effects that diverge from those of RAS stimulation in the kidney ever, one recurring theme that emerges and vasculature. In preclinical studies, activating type 1 angiotensin (AT1) receptors from the work of several laboratories in- in T lymphocytes and myeloid cells blunts the polarization of these cells toward cluding our own is that activating AT1 proinflammatory phenotypes, protecting the kidney from hypertensive injury and receptors directly on hematopoietic cells fibrosis. These endogenous functions of immune AT1 receptors temper the patho- may provide a feedback, immunosup- genic actions of renal and vascular AT1 receptors during hypertension. By counter- pressive signal to temper or limit the acting the effects of AT1 receptor stimulation in the target organ, exogenous pathogenic actions of inappropriate administration of AT2 receptor agonists or angiotensin 1–7 analogs may similarly RAS activation in the kidney, vascula- limit inflammatory injury to the heart and kidney. Moreover, although angiotensin II ture, and nervous system. Below, we is the classic effector molecule of the RAS, several RAS enzymes affect immune highlight several of the immunologic homeostasis independently of canonic angiotensin II generation. Thus, as reviewed effects of the RAS. 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. IMMUNOLOGIC EFFECTS OF GLOBAL RAS ACTIVATION J Am Soc Nephrol 28: 1350–1361, 2017. doi: https://doi.org/10.1681/ASN.2016101066 Preclinical and clinical studies using AT1 receptor blockers (ARBs) and angioten- The renin-angiotensin system (RAS) is a binding of angiotensin II (Ang II) to sin converting enzyme inhibitors critical hormonal signaling cascade en- type 1 angiotensin (AT ) receptors,8,9 (ACEIs) have indicated that global RAS 1 fl gaged in body fluid and BP homeostasis other peptides, enzymes, and receptors activation can drive in ammation in the (Figure 1). Reductions in kidney perfu- in this cascade have received increased kidney and vasculature through BP- sion stimulate the RAS with consequent scrutiny for their independent contribu- independent mechanisms. For example, renal sodium retention and intravascu- tions to developmental biology, renal quinapril therapy reduces renal glomer- fl lar volume expansion.1–3 Inappropriate and vascular function, and immunity. ular and tubular injury and in amma- activation of the RAS therefore leads to The discovery that the production of tory cell accumulation in rodent models hypertension and progression of kidney RAS components in kidney parenchy- and cardiovascular disease. Accordingly, mal cells is regulated independently of medicines that block the actions of the RAS peptide levels in the circulation Published online ahead of print. Publication date RAS are among the most effective classes introduced a paradigm shift in our un- available at www.jasn.org. of agents used to reduce BP and amelio- derstanding of how the RAS contributes Correspondence: Dr.StevenD.Crowley,Division rate diabetic and nondiabetic kidney to the pathogenesis of hypertension.10 of Nephrology, Department of Medicine, Durham VA and Duke University Medical Centers, DUMC 4–7 fi disease. Although the classically rec- Tissue-speci c regulation and functions Box 103015, Durham, NC 27710. Email: steven.d. ognized functions of the RAS to promote of the RAS are similarly evident in other [email protected] renal sodium retention and vasocon- organs including those engaged in innate Copyright © 2017 by the American Society of striction are mediated through the and adaptive immune responses. Indeed, Nephrology 1350 ISSN : 1046-6673/2805-1350 JAmSocNephrol28: 1350–1361, 2017 www.jasn.org BRIEF REVIEW 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. of immune-complex GN,13–15 whereas inflammation in the brain.18–20 In hu- elevation. Accordingly, lymphocyte or ACEI or ARB treatment ameliorates mu- man patients with CKD, RAS inhibition cytokine blockade prolongs survival rine lupus nephritis to a greater extent limits renal inflammation and oxidative and blunts hypertensive renal damage than amlodipine.16 In atherosclerosis, stress independently of BP.21 These types in RAS activation models,24 whereas ro- angiotensin converting enzyme (ACE) of experiments developed the thesis that dents lacking lymphocytes are protected inhibition attenuates the vascular global RAS activation instigates tissue from RAS-dependent hypertension and expression of the mononuclear cell che- damage in part by stimulating cellular have preserved vasodilatory and natri- mokine CCL2 and the intralesional immune responses. uretic responses.25,26 Collectively, these accumulation of inflammatory macro- Although RAS-dependent hyperten- studies would suggest that subclinical phages.17 Moreover, RAS-mediated in- sion largely accrues from activation of kidney injury or even salt retention trig- duction of the profibrotic cytokine AT1 receptors in the kidney and its vas- gered by renal AT1 receptor ligation TGF-b has been recognized as a funda- culature,22,23 upregulated immune invokes an inflammatory milieu that mental driver of scar formation in the responsesinthissettingcanalsocon- exacerbates BP elevation and tissue kidney and, more recently, autoimmune tribute to tissue injury and even BP damage.27–30 J Am Soc Nephrol 28: 1350–1361, 2017 Immunologic Effects of RAS 1351 BRIEF REVIEW www.jasn.org Indeed, experiments using mice with inflammation. For example, PRR stimula- transcription factor to direct the emer- genetic deletion of the dominant murine tion enhances proinflammatory cytokine gence of endothelial, myeloid, ery- 39,40 AT1 isoform, AT1A,havelargelycon- levels in the vasculature and microglia. throid, and lymphoid cell lineages firmed that the proinflammatory effects Within the immune system, the PRR path- from hemangioblast colonies.51 This of RAS activation accrue from stimulat- way is active in human monocytes and is biology may contribute to the develop- ing AT1 receptors in the target organ. For required in T lymphocytes for their acqui- ment of anemia in some ACEI-treated example, after bone marrow transfer be- sition of peripheral T cell markers including patients although alterations in eryth- 2 2 / 52 tween Agtr1a mice lacking the AT1A CD4 and CD8 during thymic educa- ropoietin levels also play a role. Sec- receptor and wild-type controls, suscepti- tion.41,42 Moreover, the PRR is expressed ond, ACE edits the carboxyl terminus bility to immune-mediated kidney injury on both macrophages and T cells infiltrat- of peptide antigens presented to CD8+ and renal macrophage accumulation ing the glomerulus during human crescen- T cells in the context of class I major 53 arose from AT1A receptor expression in tic GN, and renin-mediated induction of histocompatibility molecules. This the host rather than the bone marrow do- IL-6 and cyclooxygenase-2 in human function of ACE would have unpredictable 31,32 nor. In our own hands, AT1A receptor mononuclear cells requires extracellular effects on adaptive immune responses, de- expression on bone marrow cells did not signal-regulated kinase 1/2 phosphorylation pending on specific alterations in antigen influence the progression of murine lupus but not angiotensin receptor ligation.43 sequences mediated through ACE’scar- nephritis. Rather, augmented AT1 recep- These data support a new paradigm in boxypeptidase activity (Figure 2). Thus, tor activation in the glomerular podocyte which RAS components other than the ef- whereas ACE-mediated generation of triggered robust renal inflammation in fector molecule Ang II modulate inflamma- Ang II in the target organ triggers damage this model.33 Likewise, inflammation in tion in the target organ. However, the net to invoke a secondary inflammatory