BRIEF REVIEW www.jasn.org

Immunologic Effects of the - 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

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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. 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

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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 re- the atherosclerotic lesion depended on effects of renin’s classic proteolytic actions sponse, the direct actions of ACE within AT1 receptor activation in the blood vessel combined with its nonproteolytic signaling immune cells and their progenitors are rather than the bone marrow.34,35 Thus, via the PRR in inflammatory disease await more nuanced and context-specific. the effects of the RAS to promote inflam- further clarification. mation appeared to accrue from activa- tion of AT1 receptors in the kidney and ACE2/ANGIOTENSIN 1–7 vasculature rather than in infiltrating he- ACE matopoietic cells. However, these studies The immunologic effects of the alternate belied a more complex set of interactions As the dominant enzyme that converts ACE enzyme, ACE2, could accrue from between the immune system and individ- Ang I to the RAS effector molecule Ang its catabolism of Ang II or the consequent ual RAS components that became evident II, ACE promotes inflammation in the generation of Ang 1–7. By reducing Ang through deletion experiments dis- heart, kidney, and vasculature that is II levels in the kidney and vasculature, cussed below. attributable to Ang II (Figure 1). Ac- ACE2 might be predicted to blunt in- cordingly, ACE inhibition not only flammatory responses elicited by Ang ameliorates cardiac damage after myo- II–mediated hemodynamic injury. In- RENIN/PRORENIN cardial infarction and slows the pro- deed, in the murine apoE-deficient gression of proteinuric kidney disease, model of atherosclerosis, ACE2 attenu- In converting angiotensinogen to angio- but also reduces circulating and urinary ates the formation of aortic plaques in tensin I (Ang I), renin catalyzes the rate- levels of inflammatory markers.5,44–48 vivo and also limits macrophage expres- limiting step in the generation of the RAS Early studies investigating the immune sion of several proinflammmatory cyto- effector molecule, Ang II (Figure 1). Ac- functions of ACE focused on the role of kines in vitro, including TNF-a and IL-6, cordingly, renin is the proximate driver ACE in granulomatous disease. Se- after an LPS challenge, suggesting that of AT1 receptor-dependent inflamma- creted by histiocytes in granulomata, ACE2 can directly blunt the proinflam- tion in the vascular wall.34,36 However, circulating ACE became a marker to matory polarization of myeloid cells.54 in 2002, Nguyen and colleagues cloned support the diagnosis of sarcoidosis.49 These anti-inflammatory effects of ACE2 the (pro)renin receptor (PRR) through In turn, ACE inhibition could shrink depend at least in part on local reductions which renin and its precursor (pro)renin the granulomata induced by Schisto- in Ang II levels as concomitant ACE in- activate the extracellular signal-regulated soma mansoni infection, suggesting hibition ameliorates some of the tissue kinase 1/2 signaling cascade indepen- that ACE similarly contributes to the damage and immune activation attribut- dently of canonic Ang II generation.37 infectious inflammatory response.50 able to ACE2 deficiency. Consistent with Whereas the PRR is part of a Wnt/b-catenin Nevertheless, ACE, like (pro)renin, the capacity of Ang II to drive tissue fibro- signaling complex that is critical for planar has other pleiotropic effects on immu- sis, ACE2 similarly protects against kidney development,38 the PRR is also broadly ex- nity that have emerged more recently. inflammation and fibrosis in the obstruc- pressed in cardiovascular control organs First, separate from its functions as a tive uropathy model in part by limiting where its ligation can directly promote proteolytic enzyme, ACE acts as a induction of renal TGF-b expression.55

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Figure 2. ACE-mediated cleavage of MHC I peptides in antigen presenting cells modulates adaptive immunity. Cytoplasmic or exogenous antigens (in the case of dendritic cell cross presentation) are fragmented by proteasomes. Peptide products are then shuttled to the endoplasmic reticulum (ER) where ACE can alter the peptide sequence via C-terminal cleavage. After MHC I loading, the peptide is transported to the cell surface. CD8+ T cells scan the MHC I complex and, upon recognition, initiate an adaptive immune response. Alterations made by ACE to the peptide sequence can thereby alter the specificity of the immune response.

Although the notion that ACE2 attenuates glomerular injury and renal universally seen in all forms of renal blunts inflammatory responses by rais- expression of inflammatory markers in a damage as experimental kidney fibrosis ing levels of Ang 1–7 is still debated, rat MPGN model.57 Whether the bene- and AKI worsen with Ang 1–7treat- treatment with Ang 1–7 has successfully fits of Ang 1–7 accrue from activation of ment.59 Thus, the immunologic effects reduced inflammatory damage in the the putative Ang 1–7, or Mas, receptor is of Ang 1–7 may depend not only on its heart and kidney in several preclinical less clear as Ang 1–7 formulations can dose and formulation but also on disease studies. For example, Ang 1–7infusion mitigate tissue inflammation even in context, and careful translational studies limits inflammatory cardiac injury in a Mas-deficient rodents.58 Moreover, the will be required to determine if Ang 1–7 diabetic hypertensive rat model56 and favorable actions of Ang 1–7arenot represents a novel anti-inflammatory

J Am Soc Nephrol 28: 1350–1361, 2017 Immunologic Effects of RAS 1353 BRIEF REVIEW www.jasn.org therapeutic to ameliorate specific renal and upregulated renal mRNA expression able to confirm that the macrophage vascular diseases. of the kidney injury marker Ngal AT1 receptor ameliorates kidney fibrosis (Lcn2) and exacerbated podocyte by limiting IL-1 generation and dropout as detected by reduced glo- thereby abrogating IL-1 receptor stim- 64 63 AT1 RECEPTORS merular staining for WT1. Thus, acti- ulation in renal parenchymal cells. vating AT1 receptors on T lymphocytes Thus, on the basis of bone marrow chi- In the adult organism, the AT1 receptor is attenuates hypertensive injury to the kid- mera and conditional gene targeting more highly expressed in cells of the im- ney glomerulus through a BP-independent studies, AT1 receptors on myeloid and mune system than the type 2 angiotensin mechanism. Toexplain these findings, lymphoid populations play an immu- 11,60,61 + receptor (AT2) receptor. Given the CD4 T cells lacking the AT1A recep- nomodulatory role that tempers the capacity of global RAS activation to drive tor isolated from the hypertensive kid- pathogenic actions of AT1 receptors in renal and vascular inflammation during ney or spleen expressed higher levels the kidney and vasculature during hyper- hypertension, several groups have exam- of the proinflammatory cytokines tension. However, considerable work will inedtheroleofAT1 receptors on im- IFN-g and TNF-a as well as the Th1 be required to elucidate cellular signaling mune cells in regulating hypertensive transcription factor T-bet (Tbx21) pathways governing these effects and de- target organ damage through the gener- that drives expression of these cyto- velop translational approaches that ex- 2 2 / 64 ation of murine Agtr1a bone marrow kines in T cells. Thus, AT1 receptor ploit divergent, cell-specificactionsof chimeras. The Tsukuba mouse harbors stimulation on T cells suppresses AT1 receptors in patients with hyperten- the human renin and angiotensinogen T-bet–dependent differentiation of sion and/or kidney fibrosis. and therefore serves as a model the CD4+ T helper cell toward the of hypertension induced by chronic proinflammatory Th1 cell lineage. RAS stimulation. Tsukuba mouse chi- Subsequent studies revealed that T-bet AT2 RECEPTORS meras lacking the AT1A receptor on deficiency limits albuminuria, podo- bone marrow–derived cells have a pre- cyte loss, and renal Ngal expression, Actions of the AT2 receptor counteract served hypertensive response but more se- confirming a role for the Th1 immune the actions of the AT1 receptor in several vere atherosclerosis in the aorta compared response to instigate glomerular damage organ systems.68 For example, in con- 62 64,65 with wild-type transplant controls. Sim- during hypertension. trast to AT1 receptor–mediated vasocon- ilarly, in a chronic Ang II infusion model In our chronic Ang II infusion model, striction, AT2 receptor activation in the of hypertension, we found that AT1A re- the Macro KO animals lacking myeloid vasculature prompts vasodilation with ceptor–deficient bone marrow chimeras AT1A receptors also had a preserved hy- potential beneficial effects in the renal have exaggerated BP elevation, albumin- pertensive response.63 On the basis of microcirculation during pathogenic 69 uria, and accumulation of T cells and these data, AT1 receptors on T cells and conditions. In our hands and others, 60 macrophages in the kidney. Thus, in macrophages do not play a key role in BP the AT2 receptor is not highly expressed contrast to the pathogenic actions of renal homeostasis. Nevertheless, the Macro on cells of the immune system,61,63,64 and vascular AT1 receptors in hyperten- KO cohort had more severe renal tubular but has been detected on human T and 12 sion, AT1 receptors on immune cells ap- injury and interstitial fibrosis than con- NK cells. In a rat model of myocardial pear to play a protective role (Figure 3). trols after 4 weeks of hypertension. This infarction, intracardiac transfer of CD4+ + To further investigate these favorable capacity of the macrophage AT1 receptor to or CD8 T cell populations expressing actions of immune cell AT1 receptors in mitigate kidney fibrosis was similarly evi- the AT2 receptor reduced infarct size hypertension, we generated mice lack- dent in the normotensive ureteral obstruc- andimprovedcardiacfunction.70,71 63 ing the AT1A receptor selectively on T tion model, consistent with Ichikawa’s The protective effects of AT2 receptor ac- lymphocytes (TcellKO) or myeloid cells experiments using AT1A receptor–deficient tivation in the target organ can also have (Macro KO) and then subjected these bone marrow chimeras.66 Analogous to the downstream beneficial effects on the tis- mice and their wild-type littermates to effects of the AT1 receptor on T cell polar- sue’sinflammatory milieu. The develop- our Ang II–dependent hypertension ization, we found that activating the AT1 ment of a selective AT2 receptor agonist, model.63,64 The chronic hypertensive receptor on macrophages suppresses their compound 21 (C21),72 has highlighted responses were similar in the TcellKO proinflammatory M1 polarization with the potential broad anti-inflammatory and control cohorts. However, the Tcell consequent reductions in TNF and effects of AT2 receptor stimulation. For KO animals had augmented albumin- IL-1b expression. In a murine obesity example, in a rat myocardial infarction uria and exaggerated perivascular accu- model, Ma and Fogo similarly detected model, AT2 receptor stimulation with mulation of CD4+ Tlymphocytesinthe enhanced expression of several M1 C21 reduced scar size, preserved ejec- hypertensive kidney, just as seen in the markers on AT1A receptor–deficient tion fraction, and prevented upregula- 67 AT1A receptor–deficient bone marrow macrophages. M1 cytokines have been tion of the proinflammatory cytokines chimeras. Moreover, AT1 receptor defi- implicated in renal fibrogenesis, and in IL-1b and IL-6 in the border zone of the ciency on T cells during hypertension kidney crosstransplant studies we were infarcts, all of which was reversed by

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Figure 3. Functions of the AT1 receptor on immune cells. Proinflammatory stimuli drive the differentiation of M1 macrophages (left) and Th1 T lymphocytes (right) that release pathogenic cytokines such as IL-1b,TNF,andIFN-g (IFNG). In preclinical studies, activation of the

AT1 receptor on macrophages and T cells limits their differentiation toward proinflammatory lineages, thus inhibiting the production and release of these cytokines that drive hypertensive kidney injury and fibrosis.

concomitant treatment with the AT2 re- IMMUNOLOGIC EFFECTS OF RAS suppressing immunity. In this regard, 73 ceptor blocker PD 123319. AT2 recep- MANIPULATION IN HUMANS human studies confirm the favorable ef- tor activation similarly reduced renal fects of direct renin inhibition on pa- inflammation measured by TNF and The discrepant and partially indepen- rameters of immune activation. For IL-6 expression and oxidative stress dent effects of the various RAS peptides example, in 27 patients with type 1 di- in the Zucker rat model of renal in- and enzymes on immune responses abetes mellitus and no nephropathy, jury.74 Moreover, treatment of cul- should allow discrete, optimized inter- treatment with aliskerin for 30 days re- tured proximal tubule epithelial cells ventions to limit RAS-dependent inflam- duced urinary excretion of IFN-a2and 77 with C21 reduced TNF and IL-6 pro- mation in humans. AT2 receptor and Ang IL-2. Similarly, in 30 patients with hy- duction in response to LPS activa- 1–7 agonists, if carefully engineered and pertension and CKD, aliskerin treatment tion.75 The immunosuppressive effects tested in specific cardiovascular and re- for 8 weeks reduced serum C reactive 78 of AT2 receptor stimulation accrue nal disease contexts, may complement (CRP) levels. Nevertheless, from enhanced epoxyeicosatrienoic current ACEI and ARB treatment, pos- the addition of direct renin inhibitors acid formation and direct inhibition sibly by mitigating the induction of in- to ARB therapy has not yielded consis- of the NF-kBinflammatory signaling flammatory responses that can result tent improvements in clinical out- 76 79 cascade. These preclinical studies in- from blocking AT1 receptors on immune comes, diminishing enthusiasm for dicate that the immunomodulatory cells. Inasmuch as noncanonic renin/ this strategy unless alternative, more fl actions of the AT2 receptor occur prorenin signaling provokes in amma- efficacious modulators of noncanonic both within infiltrating immune cells tory responses independently of Ang II, PRR signaling can be developed. and within the target organ’sparen- direct renin inhibition may similarly On the basis of preclinical data from chymal cells. complement standard RAS blockade by others and our group, the incomplete

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85 efficacy of global AT1 receptor blockade alone. However, in these types of stud- that in the context of renal inflamma- in arresting human kidney disease pro- ies, global RAS blockade in all tissues tion, preserving a putative protective ac- 80 gression could accrue in part from in- could obscure opposing tissue-specific tion of immune AT1 receptors while hibition of AT1 receptors on immune immunologic effects, and indirect re- blocking AT1 receptors in cardiovascular cells that provokes inflammation and ductions in systemic inflammation dur- control centers may become more rele- thereby tempers the beneficial effects of ing global RAS blockade could accrue vant. Conversely, as inflammatory cells RAS blockade directly in the target organ. from the hemodynamic protection of have lower levels of AT1 receptor expres- Although the components of the RAS are target organs. sion than the kidney,64 vigorous levels of expressed in human inflammatory Consistent with these hemodynamic RAS activation may be required to in- 12 cells, examining the in vivo effects of benefits, ACEI or ARB treatment for dis- voke the protective actions of AT1 recep- activating the RAS specifically within eases localized to the blood vessel wall has tors on immune cells that partially abate these cells poses a considerable challenge. largely attenuated circulating markers of the pathogenic actions of AT1 receptors In cultures of human T cells activated in inflammation. For example, in an un- in the kidney and vasculature. vitro, Ang II did not alter production of controlled study of 77 patients with Gene polymorphism studies from pa- the proinflammatory cytokines IFN-g or known coronary artery disease, 6 months tients with autoimmune disease are con- IL-17 and had no effect on dendritic cell– of ramipril reduced circulating CRP lev- sistent with protective actions of the RAS mediated T cell proliferation.81 However, els.86 Similarly, in 27 postangioplasty pa- in immune cells. In several series of hu- in vitro stimulation of human PBMCs tients, irbesartan reduced IL-6 and CRP man patients with SLE, lower serum ACE with Ang II suppressed their generation concentrations after 3 months compared levels as a proxy for diminished systemic of TGF-b,82 despite the well documented with baseline.45 However, not all studies RAS activation have been associated with effects of Ang II to drive TGF-b expres- indicate that RAS inhibition reduces vas- more severe renal disease.91,92 Similarly, sion in kidney cells.18 Moreover, in vivo cular inflammation through effects on lower serum ACE levels in patients with captopril treatment of human kidney BP. In an observational study of 507 pa- pulmonary sarcoidosis associated with a transplant recipients enhanced TGF-b tients with stroke, ramipril treatment more vigorous immunogenic response release from their PBMCs,82 consistent was associated with lower CRP levels at to influenza vaccination.93 However, with our murine studies in which abro- the time of the stroke compared with not all human cohorts confirm this in- 87 94,95 gating AT1 receptor signals in myeloid other antihypertensive regimens. Re- verse association, and such observa- cells induced profibrotic gene expres- gardless of the mechanism, disrupting tional gene association studies must be sion programs, augmenting renal scar pathologic vascular remodeling with interpreted with caution. formation.63 RAS blockade has, on balance, improved An intriguing example of apparent In the absence of tools to modulate the parameters of systemic inflammation. immune amplification during RAS RAS selectively within human immune By contrast, in patients with hyper- blockade has been reported in patients cell lineages, studies in which patients are tension and renal inflammation, global with an idiosyncratic ARB-associated in- treated with ACEIs or ARBs reveal the net RAS blockade has had mixed effects on flammatory bowel disease, a disorder effect of concomitantly disrupting AT1 immune responses. In 29 patients with classically driven by hyperactive Th1 im- receptor signals in both the target organ hypertension and chronic GN, irbesar- mune responses. In these rare cases, and the immune system. In most cases, tan therapy for 26 weeks yielded variable treatment with the ARB olmesartan has ACEI or ARB monotherapy in patients effects on immune parameters with re- been linked to a severe immune- with hypertension has had favorable ef- ductions in circulating CRP levels but no mediated enteropathy.96–98 Consistent fects on circulating markers of inflam- significanteffectsonTNForIL-6 levels.88 with a heightened Th1 response in this mation. For example, in a randomized Moreover, in a 16-week randomized syndrome, intraepithelial CD3+ Tcell crossover trial in 45 patients with mild- study of 109 hypertensive diabetic pa- accumulations are noted in the bowel to-moderate hypertension, candesartan tients, high-dose valsartan did not re- wall, and disease responds to anti-TNF reduced plasma levels of CCL2 and TNF duce serum IL-6 or TNF levels.89 therapy. These clinical features are con- after 2 months.83 Similarly, in 20 young, Patients undergoing hemodialysis ex- sistent with our finding that mice lacking newly diagnosed patients with hyperten- hibit evidence of systemic inflammation, the AT1 receptor on T lymphocytes have sion, 3 months of therapy with losartan and in a randomized study of 15 hemo- an exaggerated Th1 response with an normalized BP and reduced the prolifer- dialysis patients,90 ramipril raised circu- augmented capacity for TNF genera- ative responses of T lymphocytes drawn lating IL-1b concentrations, consistent tion.64 The enteropathy occurs more from the circulation.84 Finally, in a with our murine studies,63 but lowered commonly in patients with other evi- randomized, crossover trial of 47 IL-10 and IL-6 concentrations. Both dence of autoimmunity, suggesting a hypertensive patients with hypercholes- ramipril and valsartan increased sys- predisposition to ARB-induced immune terolemia, the addition of losartan to temic oxidant stress measured by F(2)- activation. simvastatin for 2 months reduced isoprostane levels without modulating Randomized controlled trials of RAS CCL2 levels more than simvastatin BP during dialysis. Thus, it is possible inhibition provide some indications that

1356 Journal of the American Society of Nephrology J Am Soc Nephrol 28: 1350–1361, 2017 www.jasn.org BRIEF REVIEW preserving a low level of RAS signaling suppression in those patients with CONCLUSION may be protective. In the ONTARGET target organ damage and evidence of and NEPHRON-D studies, complete ACEI- or ARB-provoked inflammation Complementing its central role in BP ho- RAS blockade with concomitant ACEI represents a feasible alternative, particu- meostasis,the RAS has diverse andcomplex and ARB treatment led to higher levels larly in this era of precision medicine. effects on innate and adaptive immunity. of kidney dysfunction than ACEI or ARB Preclinical studies indicate that RAS in- Through coordinatedregulation of Ang II monotherapy, despite no difference in hibition concomitant with chemokine levels, the RAS proteolytic cascade affects systolic BPs between ARB treatment blockade can limit proteinuria and po- hemodynamic injury in the heart, kidney, and dual blockade.99,100 In a smaller docyte loss in CKD.104 In small human and vasculature leading to profound, double-blinded randomized study of 56 studies, lymphocyte suppression with global upregulation of inflammatory re- patients with macroalbuminuric dia- mycophenolate mofetil or even TNF sponses. However, through actions unre- betic nephropathy, combination therapy blockade can reduce BP in patients lated to Ang II, the (pro)renin receptor increased the adjusted risk for worsening with rheumatologic disease.105,106 and ACE affect the development and dif- proteinuria and increased urinary excre- Nevertheless, the risks of prolonged im- ferentiation of individual immune cell tion of CCL2 compared with ACEI or munosuppression could outweigh car- lineages, the consequences of which will ARB monotherapy.101 These trials diovascular benefits unless reserved for require further elucidation. Moreover, by would indicate that a threshold level of persistently hypertensive patients who altering the peptide sequences of antigens RAS inhibition rather than maximal, sustain renal injury and a fingerprint of presented to CD8+ T cells, ACE may have dual blockade is optimal for the treat- immune activation despite ARB or ACEI profound effects on antiviral immunity ment of hypertension and kidney therapy. For example, patients appropri- and even tumor surveillance. Although disease. ate for pilot intervention studies could activating AT1 receptors in the kidney If permitting RAS activation in im- be identified on the basis of recorded and vasculature instigates damage that mune cells is beneficial, then blocking BPs, documented albuminuria, and se- secondarily engages the immune system, RAS signals selectively within the end or- rum or PBMC levels of TNF or IL-1b in bone marrow chimera and conditional gan, such as the heart or kidney, could large captive patient cohorts such as the gene targeting studies in mice indicate ameliorate disease in these organs more Veterans Affairs health system. Further that stimulating AT1 receptors directly effectively than global, systemic RAS adoption of electronic medical records on inflammatory cells paradoxically blockade. Some human biopsy studies linked to biobanks of stored blood sam- tempers this immune activation in an support the notion that RAS blockade re- ples should facilitate the assembly of apparent feedback paradigm. This phe- duces inflammation by acting directly such cohorts. On the other hand, just nomenon cannot be easily ascribed to within the targetorgan. Forexample, anal- as intrarenal RAS augmentation occurs AT1 receptor–mediated immune cell ysis of heart biopsy specimens from 58 independently of the circulating RAS,107 “exhaustion” as we do not detect mark- patients with ischemic heart disease ran- induction of cytokine signaling path- ersofexhaustiononTlymphocytessub- domized to ramipril, valsartan, or placebo ways that promote hypertension and re- jected to chronic RAS activation.64 for 6 days before coronary bypass surgery nal damage may be circumscribed Moreover, we see divergent, pathogenic, showed that treatment with either the within the kidney65 and escape detection and protective actions of renal and T cell ACEIortheARBwasassociatedwithlower in samples of peripheral blood. Accord- AT1 receptors, respectively, in a single TNFandIL-6levelsinthecardiactissue.102 ingly, additional preclinical studies are murinemodelofAKIwellbeforeTcell RAS inhibitors with inherent specificity needed to (1) identify more selective tar- exhaustion should emerge.110 Confir- for target organs could offer one strategy gets within inflammatory signaling mation that AT1 receptor activation on to combat local inflammation while pre- cascades whose blockade during RAS in- immune cells suppresses the inflamma- serving any beneficial RAS signals in cir- hibition can reduce BP and/or protect tion and injury induced by activation of culating hematopoietic cells. For example, end organs with limited impairment of AT1 receptors in the kidney and vascu- in a small study of patients who had suf- systemic immunity, and (2) elucidate the lature would open new avenues for fered myocardial infarctions, treatment cellular sources of immune mediators novel immunomodulatory therapies to with “high–tissue penetrating” quinapril that promote hypertension and/or renal be used in conjunction with global reduced circulating CRP levels more injury during ARB or ACEI treatment. ARBs.Indeed,TNFandIL-1,bothregu- than “low–tissue penetrating” enalap- Ultimately, advances in bioengineering, lated by the immune AT1 receptor in ril.103 Although authors attributed the dif- implemented with thoughtful ethical our experiments, have been linked to ferences in efficacy to enhanced vascular guidance, may yield tissue-specific hypertension and/or vascular dys- wall penetration with quinapril, differ- therapies in humans to abrogate path- function in preclinical and clinical 25,65,106,111,112 ences in potency would offer an alterna- ogenic AT1 receptor–mediated ac- studies. Other potential tive explanation. tions in the kidney and/or vasculature anti-inflammatory RAS therapies that In the absence of tissue-specificARBs, without invoking off-target immune warrant further translational investigation 108,109 exploring targeted, low-grade immuno- activation. include Ang 1–7analogsandspecificAT2

J Am Soc Nephrol 28: 1350–1361, 2017 Immunologic Effects of RAS 1357 BRIEF REVIEW www.jasn.org receptor agonists.113 Finally, because of in Progressive Renal Insufficiency Study Group: damage and renal chemokine expression in space constraints, this review has not ad- Effect of the angiotensin-converting-enzyme MRL/lpr mice. J Pharmacol Exp Ther 307: inhibitor benazepril on the progression of 275–281, 2003 dressed important immunologic effects of chronic renal insufficiency. NEnglJMed334: 17. Hernández-Presa M, Bustos C, Ortego M, 114 the RAS effector aldosterone. Because 939–945, 1996 Tuñon J, Renedo G, Ruiz-Ortega M, Egido J: the RAS signaling cascade interacts at 7. 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Lancet 359: 995 1003, 2002 giotensinIIinrenal brosis. Hypertension 8. Ito M, Oliverio MI, Mannon PJ, Best CF, 31: 181–188, 1998 MaedaN,SmithiesO,CoffmanTM:Regu- 19. Wolf G, Mueller E, Stahl RA, Ziyadeh FN: lation of blood pressure by the type 1A an- Angiotensin II-induced hypertrophy of cul- giotensin II receptor gene. Proc Natl Acad tured murine proximal tubular cells is me- ACKNOWLEDGMENTS Sci USA 92: 3521–3525, 1995 diated by endogenous transforming growth 9. Oliverio MI, Best CF, Smithies O, Coffman factor-beta. JClinInvest92: 1366–1372, TM: Regulation of sodium balance and 1993 This work was supported by National Insti- blood pressure by the AT(1A) receptor for 20. Lanz TV, Ding Z, Ho PP, Luo J, Agrawal AN, tutes of Health grants DK087893, HL128355, angiotensin II. Hypertension 35: 550–554, Srinagesh H, Axtell R, Zhang H, Platten M, and P30DK096493; Veterans Health Ad- 2000 Wyss-Coray T, Steinman L: Angiotensin II ministration, Office of Research and Devel- 10. 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