HYPERTENSION AND THE KIDNEY (RM CAREY, SECTION EDITOR)

Renal Generation of Angiotensin IIand the Pathogenesis of Hypertension

Jorge F. Giani & Tea Janjulia & Brian Taylor & Ellen A. Bernstein & Kandarp Shah &Xiao Z. Shen & Alicia A. McDonough & Kenneth E. Bernstein &Romer A. Gonzalez-Villalobos

Published online: 6 August 2014# Springer Science+Business Media New York 2014

Abstract The existence of a complete and functional renin-angiotensin system along the nephron is widely recognized.However, its precise role in blood pressure control and, byextension, hypertension is still uncertain. While most investi-gators agree that overexpressing RAS components along thenephron results in hypertension, two important issues remain:whether the local RAS works as a separate entity or representsan extension of the systemic RAS and whether locally gener-ated angiotensin II has specific renal effects on blood pressurethat are distinct from systemic angiotensin II. This reviewaddresses these issues while emphasizing the unique role oflocal angiotensin II in the response of the kidney to hyperten-sive stimuli and the induction of hypertension.

Keywords ACE . hypertension . kidney . RAS

Introduction

The human kidney filters approximately 180 l of plasma everyday, the equivalent to 60 times the whole plasma volume of anormal individual. Said another way, by the time you finish

reading this review (in about 1 h), your kidneys will havefiltered the entirety of your plasma at least twice. Most of thefiltered volume is reclaimed because of the powerful sodiumand water retention capacity of the renal tubules and theactions of the octapeptide angiotensin II. Thus, it is not sur-prising that angiotensin II can be produced locally within thekidneys because of the activity of a complete renin-angiotensin system (RAS) expressed along the nephron. Infact, the renal RAS can play an important role in disease. Thisreviewwill discuss the evidence showing that the renal RAS ispathologically activated by renal injury and inflammation andthat this activation represents a powerful mechanism to gen-erate hypertension.

Expression of RAS Components Along the Nephron Largeamounts of angiotensinogen accumulate in the proximal tubularepithelium. Because this angiotensinogen is excreted into thetubular lumen and in the urine, many investigators believe thatit can be cleaved by tubular renin and ACE to form angiotensinII [13]. Support for this concept is provided by multipleexperiments showing that transgenic mice overexpressing hu-man, rat or mouse angiotensinogen in proximal tubular epithe-lium develop hypertension and renal injury with no apparentalterations of the systemic RAS [46]. The source of proximaltubule angiotensinogen is still a point of contention. Recently,Matsusaka et al. demonstrated that liver angiotensinogen is themain source of angiotensinogen under basal conditions, at leastin mice [7]. However, their observation does not explain theincreases of angiotensinogen mRNA in kidneys from angioten-sin II infused animals [8, 9]. As it stands today, it appears thatthe angiotensinogen in segments 1 and 2 of the proximal tubuleis of systemic origin, while the angiotensinogen in segment 3 isproduced locally. Regardless of the source, an increased urinaryangiotensinogen excretion correlates with increases in renalangiotensin II content [10]. The former observation serves asthe basis for clinical studies exploring urinary angiotensinogen

This article is part of the Topical Collection on Hypertension and theKidney

J. F. Giani : T. Janjulia : B. Taylor : E. A. Bernstein :K. Shah :X. Z. Shen :K. E. Bernstein :R. A. Gonzalez-VillalobosDepartments of Biomedical Sciences and Pathology and LaboratoryMedicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA

A. A. McDonoughDepartment of Cell and Neurobiology, Keck School of Medicine,University of Southern California, Los Angeles, CA, USA

R. A. Gonzalez-Villalobos (*)Pfizer, DSRD CoE, 274 Eastern Point Road, MS 8274-1245, Groton,CT 06340, USAe-mail: romer.gonzalezvillalobos@pfizer.com

Curr Hypertens Rep (2014) 16:477DOI 10.1007/s11906-014-0477-1

excretion in humans. Multiple studies show that patients withhypertension and several forms of renal disease display in-creased urinary angiotensinogen when compared to normalsubjects [11].

Tubular renin has at least three sources: systemic (i.e.,juxtaglomerular) renin can be filtered. Renin can also beproduced, although in small quantities, by proximal tubulecells and [12]; renin is also abundantly expressed in the distalnephron, mainly by connecting tubules and collecting ducts[1]. Multiple studies by Prieto-Carrasquero demonstrate thatdistal renin expression is augmented in several forms of ex-perimental hypertension, even in conditions when there issubstantial plasma renin suppression [13]. Recently, it wasshown that overexpressing collecting duct renin causes hyper-tension in mice [14]. Angiotensin-converting enzyme (ACE)is expressed in multiple cell types within the kidney [15].However, by far the site of highest expression is the brushborder of the proximal tubule. ACE expression has also beendetected in the distal nephron, although whether the source ofdistal ACE activity is local production or absorbed proximaltubule ACE is not clear.What is important is that ACE activityis detectable throughout the nephron and in the urine [16].Finally, AT1 receptors are ubiquitously expressed along thenephron, although particularly high concentrations are foundin the thick ascending limb [17].

The Renal RAS and the Response to Local ParenchymalInjury Experiments in Goldblatt and angiotensin II-infusedanimals showed that renal angiotensin II levels are muchhigher than those in the systemic circulation and subject tolocal independent regulation [18]. This raised the question ofwhether there was local angiotensin II production duringhypertension, even in high plasma angiotensin II states. Un-equivocal evidence in favor of this hypothesis was providedby experiments in rats infused with Val5-angiotensin II, anisoform of angiotensin II separable from endogenous angio-tensin II (Ile5-angiotensin II) by high-performance liquid chro-matography [19]. These studies demonstrated that chronicVal5-angiotensin II (exogenous angiotensin II) infusion in-duced renal Ile5-angiotensin II (endogenous angiotensin II)synthesis. In another study, the increase in renal angiotensin IIcontent normally observed in angiotensin II-infused mice wassignificantly reduced by concomitant treatment with an ACEinhibitor [20]. Thus, several lines of evidence indicate thatlocal synthesis is an important contributor to the local pool ofangiotensin II in hypertensive states.

Why does the kidney respond to increases in plasma an-giotensin II with local angiotensin II production? While theidea of a feed-forwardmechanism is not the prevailing view ofthe RAS, the renal expression of several of its components,namely tubular angiotensinogen, ACE, tubular renin, and theAT1receptor, is either augmented or sustained during severalforms of experimental and human hypertension [21]. For

instance, renal RAS upregulation is well documented in thehypertension induced by angiotensin II infusion and also bynitric oxide synthesis inhibition [22, 23]. One hypothesis toexplain this is that renal RAS activation is an alarm responseand not a physiological process. For instance, in vitro studiesdemonstrate that the proximal tubule angiotensinogen gene isactivated by several proinflammatory cytokines, including IL-6 and IFN- [2427]. These cytokines can act independentlyor synergistically with other factors, including angiotensin II,high glucose, and reactive oxygen species to upregulateangiotensinogen expression and secretion into the bathingmedia. Although angiotensinogen is the best understood ex-ample, reports indicate that, at least in rodents, ACE andtubular renin expression are also upregulated in many condi-tions associated with renal parenchymal injury. Another sug-gestion is that inflammatory cells express RAS componentsand therefore, in conditions of renal inflammation, can be-come a separate source of local angiotensin II [28, 29].

The Specific Effects of Renal Angiotensin II Experiments inthe 1970s and 1980s showed that direct application of angio-tensin I or RAS blockers (ACE inhibitors or AT1 receptorblockers) into the renal artery led to acute changes in theglomerular filtration rate (GFR) and sodium excretion[3033]. The importance of this pioneering work was sum-marized elsewhere [34]. Here we focus on experiments ingene-targeted mice as an important strategy to analyze theexact effects of renal angiotensin II. For instance, our labora-tory exploited the well-established fact that ACE is the mainsource angiotensin II in renal tissues [35]. Specifically, weanalyzed the renal response of ACE gene-targeted mice tohypertensive stimuli. One experiment was performed in micetermed ACE 9/9 in which ACE expression is strictly limited torenal tubular epithelium [18]. When exposed to chronic an-giotensin I infusion, ACE 9/9 mice showed increased levels ofrenal angiotensin II and urinary angiotensin II excretion.Moresignificantly, these mice developed hypertension similar inmagnitude to that observed in equally treated wild-type litter-mates. This experiment showed that renal tubular epithelialACE has the unique ability to increase the local concentrationand urinary excretion of angiotensin II and to induce hyper-tension even in the total absence of ACE and angiotensin II inextra-renal tissues [18].

To verify this hypothesis, separate experiments studied ACE3/3 and ACE 10/10 mice. In the ACE 3/3 mouse, ACE expres-sion is restricted mostly to hepatocytes [36]. ACE 10/10mice arean inbred line that expresses ACE exclusively inmyelomonocytic cells [37]; these animals have essentially norenal ACE. Both mouse strains have normal circulating levels ofACE. They also have normal blood pressure and normal baselinerenal morphology and function. Remarkably, the absence ofrenal ACE in the ACE 10/10 and ACE 3/3 mice significantlyreduced the hypertension in response to angiotensin II infusion (a

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high serum angiotensin II model) or to reduced nitric oxideproduction (a low serum angiotensin II model) [38, 39].

To better understand the effects of renal angiotensin II onkidney function, wemeasured sodium and urine output of wild-type and mice lacking renal ACE (ACE 10/10 mice) duringangiotensin II infusion [38]. This approach clamped circulat-ing angiotensin II to similar elevated levels. Angiotensin IIinfusion caused a transient reduction of sodium and urineoutput in wild-type mice that returned to pre-infusion levelsafter 48 h. These changes were substantially blunted in the ACE10/10 mice. After 3 days of infusion, sodium and urine outputswere similar in both groups. However, in wild-type mice,sodium balance was attained at the expense of hypertension,consistent with a major shift in the pressure-natriuresis relation-ship. Importantly, the absence of hypertension in ACE 10/10mice implies that the lack of kidney ACE prevents angiotensinII infusion from shifting the pressure-natriuresis relationship, amajor mechanism in establishing hypertension according toGuytons kidney-fluids hypothesis [39].

Similar observations were made during hypertension inducedby nitric oxide synthase inhibition with L-NAME (L-NAMEinduced hypertension) [40]. In this model, the protection againstthe hypertension by the lack of renal ACE was even morepronounced; while wild-type mice became hypertensive, the

blood pressure of ACE 10/10 mice remained essentially un-changed (Fig. 1). Sodium balance studies reveal that in L-NAME treated wild-type mice it was restored at the expense ofhypertension. In sharp contrast, ACE 10/10 mice showed anenhanced natriuretic response that allowed them to maintainnormal blood pressure values (Fig. 1). As a whole, these obser-vations support a very novel concept, namely that shifting of therenal pressurenatriuresis relationship toward hypertension ulti-mately depends on renal ACE and the angiotensin II producedlocally in the kidney, and not on systemic effects of angiotensin II.

In theory, the renal sodium dysregulation facilitated by therenal ACE/angiotensin II pathway can be induced by changesin glomerular filtration rate (GFR) and/or sodium reabsorp-tion. With this in mind, the GFR response to L-NAME wasstudied in conscious, unrestrained wild-type and ACE 10/10mice via a transcutaneous method [41]. Whereas wild-typemice responded to L-NAME with acute reductions in GFR,the GFR of equally treated ACE 10/10 mice remained un-changed. The explanation for this observation is not clear, butit suggests that the renal ACE/angiotensin II pathway is alsoimportant in modulating renal hemodynamic responses tohypertensive stimuli.

The effects of the renal ACE/angiotensin II pathway onsodium transport have also been explored. An extensive

Fig. 1 The absence of renal ACEderived-angiotensin II formationprevents the hypertension andsodium retention induced bysystemic nitric oxide synthesisinhibition. Wild-type and micelacking renal ACE (ACE 10/10)were given L-NAME, a nitricoxide synthesis inhibitor, in thedrinking water (5 mg/10 ml).Values represent meanSEM;N=610, ***P

expression analysis included the Na+/H+ exchanger (NHE3),loop of Henle Na+/K+/2Clco-transporter 2 (NKCC2), distaltubule NaCl co-transporter (NCC), epithelial sodium channel(ENaC), anion exchangers pendrin and NDBCE, andNa+/K+ATPase, among others. In both the L-NAME hyperten-sion and angiotensin II infusion models, the presence of kidneyACE was associated with increased sodium transport. Themost striking differences between wild-type and mutant micewere observed in response to angiotensin II infusion, where thepresence of kidney ACE facilitated substantial increases in abun-dance, phosphorylation, and/or processing of NKCC2, NCC,ENaC, and pendrin in the loop of Henle and the distal nephron.In the specific case of NKCC2 and NCC, the two transporterswith the most significant changes, increased abundance and/orphosphorylationwere consistent with increased in vivo transport-er activation (as measured by the response to specific blockers).Remarkably, the described changes were either totally absent orsubstantially attenuated in equivalently treated ACE 10/10 mice.Hence, while it is well established that angiotensin II regulatesNKCC2, NCC, ENaC, and pendrin, a major conclusion fromthese studies is the dominant effect of locally generated angio-tensin II in regulating sodium transport along the nephron. Thus,the evidence suggests that the renal ACE/angiotensin II pathwayserves as amaster switch for sodium transport along the nephron.

Conclusions

Emerging evidence supports an important and obligatory roleof angiotensin II generated within the kidney in hypertension.Experiments in gene-targeted mice reveal the importance ofthe renal ACE/angiotensin II pathway in eliciting sodiumretention through its positive modulatory effects on renalfiltration and sodium reabsorptive mechanisms. Further, theseeffects are largely independent of the plasma angiotensin IIstatus. This is because the protective effects of a lack of renalACE were observed even during the high plasma angiotensinII levels caused by angiotensin II infusion. Finally, we positthat a better understanding of the physiologic effects of localrenal ACE/angiotensin II will uncover important mechanisticknowledge about the origins of hypertension.

Acknowledgement The authors are supported by NIH grantsDK083785 (AMcD), R01HL110353 (KEB), and R00DK083455(RAGV), and an AHA Beginning Grant-in-Aid 13BGIA14680069(XZS).

Compliance with Ethics Guidelines

Conflict of Interest Jorge F. Giani, Tea Janjulia, Brian Taylor, EllenBernstein, Kandarp Shah, Alicia A. McDonough, Kenneth E. Bernstein,and Romer A. Gonzalez-Villalobos declare that they have no conflict ofinterest.

Xiao Z. Shen has received a grant from the AmericanHeart Association.

Human and Animal Rights and Informed Consent This article doesnot contain any studies with human or animal subjects performed by anyof the authors.

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Renal Generation of Angiotensin II and the Pathogenesis of HypertensionAbstractIntroductionConclusionsReferencePapers of particular interest, published recently, have been highlighted as: Of importance Of major importance