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Physiology and Pathophysiology of the Intrarenal - System: An Update

† † Tianxin Yang* and Chuanming Xu

*Internal Medicine, University of Utah and Veterans Affairs Medical Center, Salt Lake City, Utah; and †Institute of Hypertension, Sun Yat-sen University School of Medicine, Guangzhou, China

ABSTRACT The renin-angiotensin system (RAS) has a pivotal role in the maintenance of extra- EXISTENCE OF INTRARENAL RAS cellular volume homeostasis and blood pressure through complex mechanisms. Apart from the well known systemic RAS, occurrence of a local RAS has been docu- As opposed to the systemic RAS, the mented in multiple tissues, including the kidney. A large body of recent evidence circulation-borne endocrine system, the from pharmacologic and genetic studies, particularly those using various transgenic intrarenal RAS refers to a local autocrine/ approaches to manipulate intrarenal levels of RAS components, has established the paracrine system in the kidney which important role of intrarenal RAS in hypertension. Recent studies have also begun to involves both angiotensin-dependent unravel the molecular mechanisms that govern intrarenal RAS activity. This local and independent actions. A hallmark system is under the control of complex regulatory networks consisting of positive of intrarenal RAS is the high level of in- regulators of (pro)renin , Wnt/b-catenin signaling, and PGE2/PGE2 receptor tratubular Ang II that exceeds the plasma 10,11 EP4 subtype, and negative regulators of Klotho, , and liver X concentration. Strong evidence sug- receptors. This review highlights recent advances in defining the regulation and gests that intrarenal RAS contains all el- function of intrarenal RAS as a unique entity separate from systemic angiotensin II ements necessary to generate Ang II. generation. AGT is synthesized in the proximal tu- bule (PT) and can be secreted to the tu- J Am Soc Nephrol 28: 1040–1049, 2017. doi: 10.1681/ASN.2016070734 bular lumen12,13 oractwithinthePT.7 During systemic Ang II infusion, AGT expression in the renal cortex and uri- nary AGT excretion are elevated in an The renin-angiotensin system (RAS) has the cornerstone therapy for both dis- Ang II type 1 receptor–dependent been known for over a century, since the eases. No matter hypertension or renal (AT1R-dependent) manner.14,15 Consis- fi rst discovery of renin by Tigerstedt and disease, there is no clear evidence for in- tent with this finding, overexpression of 1 Bergman in 1898. ThesystemicRAS creased plasma renin activity (PRA), re- an intracellular cyan fluorescent Ang II requires interaction of multiple organs nin, or Ang II. Furthermore, the RAS in the PT via AT1R induces renal cortical involving liver production of angioten- interventions are capable of lowering mRNA and expression of AGT, sinogen (AGT) which is converted to an- blood pressure (BP) in the presence of without affecting circulating levels of 4 giotensin I (Ang I) by renin, a protease suppressed or elevated PRA despite a AGT or renin activity.16 Immunoreactive 5,6 produced by juxtaglomerular apparatus wide range of data variability. These renin is found in principal cells of the fi (JGA), followed by a second cleavage to ndings have led to the hypothesis that connecting segment and collecting duct angiotensin II (Ang II) by angiotensin these inhibitors may exert a large part of (CD) of both murine and human kidneys converting enzyme (ACE) located on their effect at a local level. the surface of lung endothelium. Apart The general knowledge of intrarenal from the well known systemic RAS, pro- RAS has already been covered by a num- Published online ahead of print. Publication date duction of multiple RAS components ber of comprehensive reviews.7–9 The available at www.jasn.org. has been found in a variety of tissues major objective of this article is to review Correspondence: Dr. Tianxin Yang, University of including the kidney.2,3 Inappropriate recent advances in defining the intra- Utah and Veterans Affairs Medical Center, Division of Nephrology and Hypertension, 30N 1900E, RM activation of intrarenal RAS has been renal RAS, including its function, and 4C224, Salt Lake City, UT 84132. Email: Tianxin. recognized as an important mechanism positive and negative regulators in the [email protected] for hypertension and renal disease. To settings of hypertension and renal Copyright © 2017 by the American Society of date, the anti-RAS regimen represents injury. Nephrology

1040 ISSN : 1046-6673/2804-1040 JAmSocNephrol28: 1040–1049, 2017 www.jasn.org BRIEF REVIEW secreted to tubular lumen in response to the liver as reflected by reduced circulating (3/3) or macrophage-specific c-fms pro- salt depletion.17 Subsequently, CD re- AGT level. Therefore, more vigorous moter (10/10). Therefore, it remains un- nin is shown to be upregulated under studies are needed to determine the con- certain whether the BP phenotype is pathologic conditions such as Ang II– tribution of intrarenal AGT versus liver directly related to the lack of ACE expres- induced hypertension18 and diabetes.19 AGT to the overall control of BP as well sion in the kidney versus the blood vessels Both ACE and AT1R are found abun- as kidney injury. or other tissues. To address this issue, the dantly throughout the apical nephron use of a nephron-specific deletion ap- surface. Direct evidence for local synthe- proach will be needed. sis of Ang II is demonstrated by using ROLE OF INTRARENAL RAS IN Studies using renal crosstransplanta- radiolabeled Ang II.20 Although circulat- HYPERTENSION tion demonstrated a significant role of re- ing 125I-Ang II is accumulated in the re- nal AT1R in BP regulation independent of nal tissue sites, the endogenous renal Several lines of pharmacologic and genetic aldosterone.37 Furthermore, conditional Ang II levels are up to 100 times higher evidence demonstrate an essential role of deletion of AT1R in the PT reduced base- than the plasma levels of endogenous intrarenal RAS in the pathogenesis of line BP and attenuated Ang II–induced Ang II.20 This result was further vali- experimental hypertension. When ACE hypertension.38 In the PT, AT1R activa- dated by the substitution of isoleucine inhibitor lisinopril was administered sys- tion appears to primarily target Na+/H+ (Ile[5] Ang II) at position five with valine temically, Ang II–infused mice became exchanger 3 to induce Na+ retention and (Val[5]-Ang II).21 normotensive with attenuation of the up- hypertension.7 The complexity of intrarenal RAS regulation of components of intrarenal ThefunctionalroleofCDreninhasbeen stems from the evidence supporting the RAS, particularly CD renin, ACE, and examined by Ramkumar et al.,whogener- circulating source of intrarenal RAS AT1R.32,33 Despite the limitations of the ated mice with CD-specific overexpression components. Nearly all major compo- systemic approach, this study provides or deletion of renin.39,40 Overexpression of nents of the RAS including AGT, prore- the first functional evidence that the pres- renin in the CD causes spontaneous hyper- nin, renin, Ang I, and Ang II will be sor response of the end product Ang II re- tension.40,41 Although deletion of renin in filtered by the glomerulus and taken up lies on the upstream enzyme ACE which the CD didn’t produce major disturbances by the PT. The uptake of circulating Ang drives in situ Ang II synthesis. Subsequent in Na+ and water balance and BP,the null II by the PT is mediated by AT1R22–27 as studies using genetic approaches to mice were protected against Ang II– well as the multiligand endocytic recep- manipulate a key component of the RAS induced hypertension.39 These results sup- tor megalin.28,29 Besides Ang II, other at the level of the whole nephron or a spe- port an important role of CD renin in BP RAS components including AGT, prore- cific nephron segment greatly facilitate un- regulation. nin, Ang I, and Ang II are also taken up derstanding of the role of intrarenal RAS in As discussed above, the functional bythePTthroughthesamemegalin- hypertension. Bernstein’sgroupgenerated contribution of intrarenal RAS to hyper- dependent mechanism.28,29 The semi- mice lacking renal ACE but having suffi- tension is tested mostly by using the Ang nal work by Matsusaka et al. demonstrates cient ACE in other tissues (termed ACE 3/3 II–infusion model which is of limited - hepatic origin of intrarenal AGT5,30; renal and ACE 10/10) that were able to maintain evance due to the nonphysiologic doses of AGT protein and Ang II levels are unaf- normal serum levels of Ang II and normal Ang II. In fact, alteration of intrarenal RAS fected by renal-specific AGT deletion us- kidney structure and BP under basal con- has been documented in several other ingtheKAP-Crebutaresignificantly dition.34 The genetic ablation of renal ACE models of experimental hypertension, reduced by liver-specific AGT deletion. A remarkably attenuated the pressor re- such as Dahl salt-sensitive rats;42 two- caveat is that urinary AGT is reduced (by sponse to Ang II infusion at 400 ng/kg kidney, one clip Goldblatt hypertension;43 approximately 50%) in renal-specific per minute, accompanied with reduced and spontaneously hypertensive rats.44 AGT knockout (KO) mice not in liver- renal Ang II content and suppressed ex- These models have a better relevance to specific AGT KO mice. Furthermore, the pression of renal Na+ transporters.35 human hypertension. Defining the func- valuable models are only analyzed under Additionally, ACE 10/10 mice were also tional role of intrarenal RAS in each of basal condition and after podocyte in- protected against L-NAME–induced hy- these models is expected to offer new per- jury.5,30 These results can’t rule out the pertension.36 Together, these results spectives on the pathophysiology of intra- possible role of intrarenal AGT under suggest that ACE-dependent activation renal RAS during hypertension. other physiologic or pathologic condi- of intrarenal RAS may represent a com- tions. Recently, another strain of renal- mon pathway leading to pressor re- specific AGT KO mice generated by using sponses to different hypertensive stimuli. ROLE OF INTRARENAL RAS IN an inducible Pax8-rtTAsystem shows a re- Of note, these models were generated by RENAL DISEASE markable reduction of urinary AGT asso- using a promoter-swamping strategy so ciated with hypotension.31 However, this that the control of ACE expression is An inappropriate activation of intrarenal study is limited in that the Pax8-rtTA sys- switched from the endogenous ACE pro- RAS has been implicated in a variety of tem also causes partial deletion of AGT in moter to liver-specific albumin promoter animal models of renal disease, such as

J Am Soc Nephrol 28: 1040–1049, 2017 Intrarenal RAS 1041 BRIEF REVIEW www.jasn.org

5/6 nephropathy, adriamycin nephrop- protein, and a short cytoplasmic do- PRO2071 administered via intramedul- athy, unilateral ureteral obstruction,45 main.54 The extracellular domain is cleaved lary infusion technique remarkably sup- and polycystic kidney disease,46 as an to generate a soluble form of PRR (sPRR) pressed the increases in urinary and initial response to hypoperfusion and via furin or ADAM19.55 This cleavage re- renal medullary renin activity during an important driver of the disease sults in three isoforms: the full length Ang II–induced hypertension.72 In vitro progression.47,48 The upregulation of PRR, sPRR, and the intracellular domain evidence further demonstrated that the multiple RAS components was usually M8.9. It is increasingly evident that PRR action of PRO20 in inhibiting renin ac- detected in the absence of increased serves a multitude of functions in regu- tivity was direct.72 In agreement with PRA or plasma Ang II.47 Urinary AGT lating embryogenesis, balancing sodium these results, CD-specific deletion of has been shown to be a strong predic- and water, modulating acid secretion, PRR reduced the basal urinary renin ac- tor of intrarenal RAS activity and etc.56–60 Of note, complete PRR deletion tivity by approximately 40% and almost renal injury in both animal and clinical in vertebrates leads to developmental al- completely abolished its response to Ang studies.49–51 terations and early embryonic lethality II at 300 ng/kg per minute, in parallel Todate, the use of RAS inhibitors such probably as a result of PRR’srolein with the suppressed hypertensive re- as ACEi or AT1 blockers remains the cor- regulation of vacuolar H+-ATPase and sponse.73 This BP phenotype was similar nerstone therapy for amelioration of al- Wnt/b-catenin signaling.61 Moreover, to that of nephron PRR KO mice gener- buminuria andrenal disease progression. nephron-specific deletion of PRR causes ated by Ramkumar et al. when Ang IIwas Yet, there is no clear evidence for en- severe autophagic defects in renal med- infused at 600 ng/kg per minute.74 How- hancement of systemic RAS in patients ullary tubules and acidosis.62 ever, another strain of nephron PRR KO with renal disease. Along this line, al- The association between PRR and model generated by Trepiccione et al.62 though ACEi treatment may acutely RAS has been extensively investigated exhibited normal BP response to Ang II lower circulating Ang II, its long-term but highly debated. Since its first identi- at 1 mg/kg per minute; renal Ang II level therapy in a subset of patients raises fication from human mesangial cells, in these null mice was also unaltered. Ang II or aldosterone concentrations PRR was thought to be a component of The exact reason for this discrepancy is back to the baseline level.52 Overall, the RAS on the basis of in vitro evi- unclear but could be related to differ- the concept of intrarenal RAS in renal dence.53 However, subsequent animal ences in experimental protocols such as disease has been well established. studies were unable to prove the renin- the doses of Ang II. However, a number of issues still need regulatory role of PRR.63 In particular, Despite the emphasis on the potential to be resolved. For example, the precise overexpression of human PRR failed to renin-regulatory role of PRR as discussed intrarenal sites of RAS activation during affect tissue Ang II concentrations.64 above, it is increasingly evident that PRR renal injury and the detailed regulatory The definitive evidence for PRR as a com- can also act in an RAS-independent mechanisms still largely remain elusive. ponent in Wnt/b-catenin signaling during manner. In cultured mpkCCD cells, Furthermore, most studies in this area embryogenesis56,65 and as an accessory activation of PRR by prorenin in the are limited in their descriptive or correl- protein of vacuolar ATPase66 further nanomolar range induced epithelial so- ative nature. The precise contribution of questioned its role in RAS regulation. dium channel activity, an effect that intrarenal RAS to renal disease as com- Unraveling this issue has been difficult was unaffected by AT1 blockade.75 pared with that of systemic RAS needs to due to the controversial PRR inhibitor This result was recapitulated by using be determined by functional studies, par- HRP67 and also the lack of viable PRR freshly isolated cortical CD with single- ticularly those using mice with genetic knockout mice. channel patch-clamp recording.74 In manipulations of RAS components in a Within the kidney, PRR is predomi- contrast, renin was largely ineffective tissue-specific manner without perturbing nantly expressed in the intercalated cells in activating the Na+ channel. The in systemic RAS. of the CD.68 The expression of PRR in vitro data favors prorenin, but not renin, the CD is stimulated by chronic Ang II as a candidate physiologic ligand of infusion69 or sodium depletion.59,60 In PRR. However, it remains elusive POTENTIAL REGULATORS OF cultured CD cells, PRR expression was whether the prorenin/PRR interaction INTRARENAL RAS stimulated by low salt or Ang II and the truly occurs in vivo.PRR’s nanomolar stimulation was potentiated by the com- affinity for prorenin/renin is many or- (Pro)Renin Receptor as a Positive bined treatments.70 In light of the colo- ders of magnitude above their levels in Regulator of Intrarenal RAS calization of PRR with renin in the CD, blood.76 Indeed, deletion of PRR in the In 2002, Nguyen et al. cloned a specificre- it is conceivable that PRR may regulate CD or the nephron produces a urine ceptor for prorenin and renin, termed (pro) renin activity in the distal nephron, concentrating defect that is not seen in renin receptor (PRR).53 PRR is a unique particularly during Ang II–induced the CD renin KO model.39 Future stud- 350–amino acid transmembrane protein hypertension. ies are needed to determine whether consisting of a large N-terminal extracellu- Functional studies showed that a prorenin or renin is the true physiologic lar domain, a single transmembrane newly developed PRR decoy inhibitor ligand of PRR.

1042 Journal of the American Society of Nephrology J Am Soc Nephrol 28: 1040–1049, 2017 www.jasn.org BRIEF REVIEW

PGE2/EP4 Pathway as a Positive cAMP/PKA, phosphatidylinositol 3-kinase, signaling. This raises a question as to Regulator of Intrarenal RAS and AKT.88,89 Among these candidate whether Wnt/b-catenin signaling affects E series prostaglandins (PGs) have long signaling mechanisms downstream of EP4 other components of the protective RAS been recognized as important regulators receptors, cAMP/PKA, but not AKT or axis such as the ACE2/Ang1-7/MasR axis. of renin secretion from the JGA.77–79 In phosphatidylinositol 3-kinase, is shown to Additionally, the PRR also con- early studies in the isolated rabbit JGA, mediate the upregulation of PRR in the CD tains multiple T cell factor/lymphoid renin secretion in response to low NaCl cells.87 enhancer–binding factor binding sites was virtually abolished by nonspecific The fluid-retaining and prohyperten- in its promoter region, raising a possibility cyclooxygenase (COX) inhibition with sive action of EP4 receptors in the distal that PRR may also be a target gene of flufenamic acid or flurbiprofen.80 Subse- nephron is opposite to the well recog- Wnt/b-catenin signaling. On the other quently, a large body of experimental evi- nized vasodilatory property of this EP hand, Ang II stimulates b-catenin sig- dence demonstrated that PGE2 derived subtype. In most vascular beds, PGE2 naling in cultured M-1 cortical CD cells from COX-2 serves as a dominant mech- functions as a vasodilator to buffer the leading to enhancement of fibronectin anism in mediating renin secretion from action of vasoconstrictive stimuli such and collagen I as well as cyclin D1 and 97 the JGA via EP2 and EP4 receptors which as Ang II. Central to the buffering actions c-. Therefore, there appears to be a 81,82 signal through the cAMP pathway. of PGE2 are the vasodilatory EP4 recep- mutually stimulatory relationship be- Besides the JGA, the CD is another tors found in both vascular smooth mus- tween Ang II and Wnt/b-catenin signal- major site of both production and action cle cells and endothelial cells. Endothelial ing during renal fibrosis. of PGE2. Among the microdissected EP4 receptors contribute to the acute The complex relationship between nephron segments, the highest amount vasorelexation of aortic rings induced by Wnt/b-catenin signaling and intrarenal 83 of PGE2 was detected in the CD. At the PGE2 through cGMP-dependent dephos- RAS is also reflected by PRR as an up- 495 distal nephron, PGE2 exerts complex phorylation of eNOS at Thr .Itwasre- stream component of the Wnt/b-catenin rolesinregulationofNa+ and water cently shown that inducible vascular pathway.56,65 We recently reported that fi transport depending on a speci cEP smooth muscle cell EP4 deletion impairs sPRR is produced from intercalated cells 84 subtype. The PGE2/EP4 pathway PGE2-induced mesentery artery relaxa- of the CD and acts in a paracrine man- is well recognized as an antidiuretic tion but fails to affect Ang II–induced hy- ner to interact with principal cell mechanism85,86 that complements vaso- pertension.90 This result suggests that frzzled-8 (FZD8), leading to activation pressin (AVP) action in the CD. Recent vascular EP4 receptors may be less impor- of b-catenin pathway and thus increas- 87 pharmacologic and conditional EP4 tant for BP regulation despite their role in ing AQP2 transcription and urine con- knockout studies86 provide compelling regulation of vascular tone. centration.98 On the basis of these evidence to support antidiuretic action of observations, we propose the following EP4 receptors in the CD which is medi- Wnt/b-Catenin Signaling as a hypothetic model: Wnt/b-catenin sig- ated by upregulation of AQP2 expression. Positive Regulator of Intrarenal RAS naling pathway and intrarenal RAS Although most of the previous studies Wnt/b-catenin signaling is an evolu- may interact with each other to form focused on the direct action of PGE2 in tionarily conserved signaling cascade a positive feedback loop where PRR regulation of tubular transport, recent that plays a pivotal role in regulating em- upregulates the b-catenin pathway 91,92 studies suggested that the PGE2/EP4 path- bryogenesis and tissue hemostasis. that in turn stimulates expression of way may modulate CD function via apre- Emerging evidence demonstrates that multiple RAS . Activation of this viously undescribed mechanism involving activation of Wnt/b-catenin signaling positive feedback loop may underlie concomitant activation of PRR and local underlies pathogenesis of CKD, includ- pathophysiology of hypertension and renin response in the distal nephron.72,87 ing diabetic nephropathy, polycystic renal injury. The capability of EP4 to independently kidney disease, chronic allograft ne- stimulate PRR and renin make it an effec- phropathy, etc.93–95 Alinkbetween Klotho as a Negative Regulator of tive regulator of intrarenal RAS leading to Wnt/b-catenin signaling and intrarenal Intrarenal RAS increased fluid reabsorption in the distal RAS is suggested by Zhou et al. who Klotho is a well known antiaging gene as nephron. This mechanism contributes to used a bioinformatics approach to dem- highlighted by the prominent ageing phe- physiologic maintenance of fluid balance onstrate that b-catenin targeted putative notype of Klotho mutant mice, including during water deprivation.87 The discovery T cell factor/lymphoid enhancer– shortened lifespan and cardiovascular dis- 99 of the PGE2/EP4/PRR pathway in the distal binding factor binding sites found in ease. Within the kidney, Klotho is selec- nephron is also of importance in BP regu- promoter regions of multiple RAS genes tively expressed in the distal convoluted lation. Our studies suggest that inap- including AGT, renin, ACE, AT1R, and tubule and the PT, serving as an obligatory propriate activation of this pathway AT2R.96 It is interesting to note that de- coreceptor for fibroblast growth factor contributes to Ang II–induced hyperten- spite their opposite roles in renal physi- 23100 to control phosphate reabsorption. 72 sion. EP4 receptors signaling works ology and pathophysiology, AT1R and Apart from the involvement in phosphate through a number of pathways involving AT2R are both targeted by Wnt/b-catenin metabolism, Klotho exerts a multitude of

J Am Soc Nephrol 28: 1040–1049, 2017 Intrarenal RAS 1043 BRIEF REVIEW www.jasn.org beneficial activities against hypertension crosstalk between nuclear receptors and protection. Indeed, multiple small clin- and renal disease.45,99,101–103 the RAS may exist. ical studies showed an inverse associa- Increasing evidence demonstrates VDR is a well established negative reg- tion between serum vitamin D levels and that the renoprotective action of Klotho ulator of the RAS.110,111 Multiple clinical hypertension.117–119 However, recent is conferred through inhibition of intra- studies revealed an inverse relationship intervention trials reveal no significant renal RAS. In various rodent models of between plasma 1,25 (OH) 2D3 concen- effect of vitamin D supplementation on renal disease including 5/6 nephropathy, trations and the BP and/or plasma renin BP in hypertensive patients.120–123 As adriamycin nephropathy, and unilateral activity in hypertensive patients as well noted by Beveridge et al.,124 these trials ureteral obstruction, renal Klotho expres- as in normal subjects.112–114 More defin- have a number of limitations. For exam- sion is suppressed but RAS components itive evidence linking VDR and the RAS ple, the largest trials to date enrolled are upregulated; administration of exoge- came from the cardiovascular pheno- only a few hundred patients. Other limi- nous Klotho through hydrodynamic- type of VDR null mice that displayed tations of these trails include limited rep- based gel ameliorates renal pathologies hypertension and cardiac hypertrophy resentation by black individuals and short associated with abolishment of the in- associated with increases in renin and duration of the studies. It is known that duction of RAS components.45 It has Ang II levels in the plasma as well as in blacks in the United States have higher further been shown that Klotho may in- renin,AGT,andAT1R,andPRRinin- rates of hypertension and cardiovascular hibit intrarenal RAS by targeting Wnt/ flammatory cells.109,110 Although this disease associated with lower circulating b-catenin signaling as suggested by the model doesn’t allow differentiating the levels of 25-hydroxyvitamin D as com- observation that Klotho directly binds involvement of systemic versus local pared with whites.125 Therefore, larger tri- multiple Wnts, including Wnt1, Wnt4, RAS, the renin response to low salt and als with improved representations by and Wnt7a, to block Wnt-triggered nu- volume stimuli, a measurement of sys- blacks for a longer duration of treatment clear translocation of b-catenin.104 temic RAS, remains intact. At cellular will be needed. Another consideration is These observations have been extended level, VDR directly suppresses renin that the inconsistent results may be related by the study of Zhou et al.,whoshowed gene transcription by interfering with to varied vitamin D dosages. Lastly, al- that Klotho exerted a direct inhibitory cAMP responsive elements in the renin though BP is the primary outcome of effect on aldosterone synthesis in adre- gene promoter.115 In rats with 5/6 ne- these trials, the effect of vitamin D supple- nal glands.105 It is likely that Klotho may phrectomy, VDR activation by paricalcitol mentation on cardiovascular events and exert a multitude of actions to mitigate decreases expression of multiple RAS renal disease remains unclear. the activation of intrarenal RAS as well genes including renin, AGT, AT1R, and LXRs heterodimerize with the reti- as systemic aldosterone production. PRRintheremnantkidneyandim- noid X receptor to regulate transcription Overall, strong evidence demonstrates proves hypertension and kidney in- of target genes involved in cholesterol, the suppression of renal Klotho expres- jury.116 These results seem to suggest fatty acid, and glucose metabolism.126–128 sion in renal disease and more vigorous that VDR may primarily target the local LXRs have an established role in re- functional studies are needed to define RAS to confer cardiovascular and renal verse cholesterol transport which leads the renoprotective action of this antiag- ing protein as well as its relationship with intrarenal RAS.

Nuclear Receptors as Regulators of Intrarenal RAS The family of transcrip- tion factors acts primarily via interacting with consensus elements in the pro- moter regions of the target genes and plays diverse and important roles in de- velopment and the regulation of normal physiologic functions, particularly energy metabolism.106 A number of nu- clear receptors such as peroxisome pro- Figure 1. Schematic illustration of regulatory networks that control intrarenal RAS activity. liferator–activated receptors,107,108 liver This local system is subjected to tight control by complex regulatory networks consisting of X receptor (LXR),98 and vitamin D re- both positive regulators of (pro)renin receptor, Wnt/b-catenin signaling, and the PGE2/EP4 109 ceptor (VDR) have been implicated in pathway, and negative regulators of fibroblast growth factor 23/Klotho, vitamin D/VDR, theregulationofplasmavolumeand and LXRs. Imbalance of the two opposing regulatory networks may be an important de- electrolyte homeostasis, a primary func- terminant of intrarenal RAS activity. FGF23, Fibroblast Growth Factor 23; LXR, liver X re- tion of the RAS. It is conceivable that a ceptor; VDR, vitamin D receptor.

1044 Journal of the American Society of Nephrology J Am Soc Nephrol 28: 1040–1049, 2017 www.jasn.org BRIEF REVIEW to cholesterol efflux from peripheral tis- basis for integrative control of intrarenal 7. Zhuo JL, Ferrao FM, Zheng Y, Li XC: New sues to the liver.129 We recently discov- RAS may offer new perspectives on both frontiers in the intrarenal renin-angiotensin system: A critical review of classical and new ered that administration of an LXR pathophysiology and therapy for hyper- paradigms. Front Endocrinol (Lausanne) 4: against TO901317 in mice induces poly- tension and renal disease. Optimism 166, 2013 uria, polydipsia, hypo-osmotic urine, has been generated from the therapeutic 8. Kobori H, Nangaku M, Navar LG, Nishiyama and downregulation of renal AQP2 ex- potential of new inhibitors of PRR A: The intrarenal renin-angiotensin system: pression, all indicative of nephrogenic di- (PRO20)72 and Wnt/b-catenin signaling From physiology to the pathobiology of 98 133 hypertension and kidney disease. Pharma- abetes insipidus. This observation (ICG-001), and activators of LXR col Rev 59: 251–287, 2007 134 reveals a novel diuretic role of renal (TO901317) and Klotho (soluble 9. Navar LG, Prieto MC, Satou R, Kobori H: LXRs. This study further provides a Klotho)135 in cardiovascular and/or re- Intrarenal angiotensin II and its contribution mechanism by which LXRs control nal diseases. In addition, the clinical im- to the genesis of chronic hypertension. Curr – urine concentrating capability via sup- plication is also suggested by circulating Opin Pharmacol 11: 180 186, 2011 101 136,137 10. Navar LG, Imig JD, Zou L, Wang CT: Intra- pressing renal PRR/sPRR and intrarenal levels of sPRR and soluble Klotho renal production of angiotensin II. Semin 72,130 RAS. This concept aligns well with as a predictor of a decline of renal function Nephrol 17: 412–422, 1997 the observation that chronic TO901317 in patients with CKD. 11. Navar LG, Nishiyama A: Why are angioten- treatment suppresses the induction of sin concentrations so high in the kidney? – renin, AT1R, and ACE in the heart and Curr Opin Nephrol Hypertens 13: 107 115, 2004 kidney induced by a nonpressor dose of ACKNOWLEDGMENTS 12. Niimura F, Okubo S, Fogo A, Ichikawa I: isoproterenol in wild-type but not Temporal and spatial expression pattern of LXRa KO mice.131 The RAS-inhibitory This work was supported by National Institutes the angiotensinogen gene in mice and rats. – and diuretic activities of TO901317 are of Health grants DK104072 and DK094956, Am J Physiol 272: R142 R147, 1997 fi likely ascribed to LXRa. However, dur- 13. Ingel nger JR, Zuo WM, Fon EA, Ellison KE, Veterans Affairs Merit Review from the Depart- Dzau VJ: In situ hybridization evidence for ing an acute setting, LXR activation ment of Veterans Affairs, and National Natural angiotensinogen messenger RNA in the rat stimulates renin expression at the Science Foundation of China grants 91439205 proximal tubule. An hypothesis for the in- JGA.132 The underlying mechanism and 31330037. T.Y. is Research Career Scientist in trarenal renin angiotensin system. JClin – and physiologic significance of the the Department of Veterans Affairs. Invest 85: 417 423, 1990 distinct effects of LXR activation on 14. Kobori H, Harrison-Bernard LM, Navar LG: Expression of angiotensinogen mRNA and RAS under the two different experimen- protein in angiotensin II-dependent hyper- tal settings certainly warrant further DISCLOSURES tension. JAmSocNephrol12: 431–439, investigation. None. 2001 In conclusion, a large body of exper- 15. 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