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Succinate Receptors in the Kidney

Peter M.T. Deen and Joris H. Robben

Department of Physiology, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands

ABSTRACT The G protein–coupled succinate and ␣-ketoglutarate receptors are closely related to nyl-CoA synthetase and subsequently the family of P2Y purinoreceptors. Although the ␣-ketoglutarate receptor is almost converted by succinate dehydrogenase exclusively expressed in the kidney, its function is unknown. In contrast, the succinate to generate fumarate. Because the suc- receptor, SUCRN1, is expressed in a variety of tissues, including blood cells, adipose cinate dehydrogenase complex is part of the tissue, liver, retina, and the kidney. Recent evidence suggests SUCRN1 and its succi- electron transport chain in the mitochon- nate ligand are novel detectors of local stress, including ischemia, hypoxia, toxicity, drial membrane (complex II; Figure 2), its and hyperglycemia. Local levels of succinate in the kidney also activate the renin- activity indirectly depends on the avail- angiotensin system and together with SUCRN1 may play a key role in the develop- ability of oxygen. As such, in situations ment of hypertension and the complications of diabetes mellitus, metabolic disease, when oxygen tension is low, succinate and liver damage. This makes the succinate receptor a promising drug target to accumulates because of low activity of counteract an expanding number of interrelated disorders. succinate dehydrogenase or other en- zymes in the electron transport chain J Am Soc Nephrol 22: 1416–1422, 2011. doi: 10.1681/ASN.2010050481 that affect its activity.5–7 Low oxygen states, such as ischemia8 or exercise9 also increase circulating levels of succinate. G protein–coupled receptors (GPCRs) are ever, GPR91 and GPR99 activate specifi- The effect of low oxygen states on suc- proteins in the plasma membrane harbor- cally through the Krebs cycle intermediates cinate levels is also obvious in rats ␣ ing seven transmembrane spanning do- succinate and -ketoglutarate (also called anesthetized with 100% CO2 instead of mains. They are activated by a wide variety oxoglutarate), respectively.3 There- oxygenated isoflurane; succinate levels of moieties including peptides, lipids, pu- fore, the gene encoding GPR91 was re- increased from 7 to 40 ␮M in the left rines, chemokines, odorants, and light. named SUCNR1 (succinate receptor 1), ventricle and up to 173 ␮M from low- Based on sequence homology to known re- whereas the gene encoding GPR99 was re- oxygen blood collected from the vena ceptors, the sequencing of the human ge- named OXGR1 (for oxoglutarate receptor 1). cava.10 nome accelerated the identification of The tissue distribution of SUCRN1 and Alternatively, other changes in energy many novel GPCRs, now numbering OXGR1 are highly expressed in the kidney.3,4 balance affect the production and release Ͼ800 family members. Many of these Although mRNA encoding OXGR1 is de- of succinate, particularly in animal mod- novel receptors have no known ligands and tected in the renal distal convoluted and con- els of diabetes mellitus,11 metabolic dis- therefore are known as orphan GPCRs. necting tubule, no function is known as yet. ease,10 and liver damage.12 During chronic In 2001, a cluster of six GPCRs was Several physiologic roles SUCNR1 have hyperglycemia, the high activity of the identified on chromosome 3q24–3q25, in- emerged, and we will focus here on its signal- Krebs cycle increases the Hϩ gradient cluding the four orphan receptors GPR86, ing in the kidney and its involvement in the across the mitochondrial membrane (Fig- GPR87, H963, and GPR91.1 The latter development of hypertension in diabetes shares high sequence homology with the mellitus. Published online ahead of print. Publication date family of P2Y purinoreceptors. Shortly available at www.jasn.org. thereafter, another novel receptor of this Correspondence: Dr. J. H. Robben, 286 Department subfamily was identified on chromosome REGULATION OF SUCCINATE of Physiology, Nijmegen Centre for Molecular Life Sci- 13q32.2, GPR99,2 showing high sequence LEVELS ences, Radboud University Nijmegen Medical Centre, 6500 HB Nijmegen, The Netherlands. Phone: 31- homology with GPR91 and P2Y receptors 2436-13684; Fax: 31-2436-16413; E-mail: j.robben@ (Figure 1). Thus, GPR91 and GPR99 might Succinate is a well-known intermediate in fysiol.umcn.nl be expected to activate on contact with pu- the tricarboxylic acid (Krebs) cycle, where Copyright © 2011 by the American Society of rinergic compounds. Surprisingly, how- it is formed from succinyl-CoA by succi- Nephrology

1416 ISSN : 1046-6673/2208-1416 J Am Soc Nephrol 22: 1416–1422, 2011 www.jasn.org BRIEF REVIEW

P2Y12 P2Y13 Outer membrane P2Y14 ATP P2Y10 synthase H+ H+ H+ P2Y5 Cyt c P2Y8 P P2Y11 I III IV II OXGR1

SUCNR1

P2Y1 + + ADP H ATP NAD NADH O2 H2O P2Y2 + + Pi H+ P2Y4

P2Y6 Citric acid Figure 1. Phylogenetic tree of the family cycle of P2Y purinergic receptors. Amino acid sequences encoding human P2Y receptors H OO Fumarate Succinate were aligned, resulting in a phylogenetic 2 2 tree based on closest sequence homology.

II ure 2), inhibiting individual complexes of IV IIIP I Inner membrane the electron transport chain including suc- 6 Cyt c cinate dehydrogenase. This results in the H+ H+ H+ intracellular accumulation and eventually release of succinate.

Figure 2. Generation of succinate in mitochondria. Succinate is an intermediate in the SUCNR1 IS A LOCAL SENSOR OF citric acid cycle and is converted by succinate dehydrogenase (also called complex II) to ϩ STRESS fumarate. When high H gradients over the inner membrane are present, or when the oxygen pressure is low, complexes I, II, III, and IV will be inhibited, leading to accumu- Quantitative PCR assays show mRNA lation of succinate. See text for more details. encoding SUCNR1 in kidney, liver, and spleen,3 and a subsequent study con- adenylate cyclase to form cAMP.4 Be- idly,12,13 suggesting that SUCNR1 serves firmed its expression in kidney and liver, cause increased succinate levels are found as an early detector of hepatic stress or as well as in white adipose tissue.4 Subse- in rodent models of diabetes mellitus and damage. Application of ischemia in a quently, several studies described the metabolic syndrome,10,11 high succinate perfused liver model increases succinate function of SUCNR1 in specific cell types levels may prevent lipolysis in states when levels of the perfusate 14-fold to approx- in these tissues. Although its detailed fuels such as glucose and free fatty acids are imately 1 mM.12 Moreover, HSCs treated function remains to be established in abundant. with succinate show increased levels of a most settings, it is clear this receptor is a myofibroblastic marker compared with detector of disturbances in energy bal- Stellate Cell Activation in Liver inactive control cells, indicating that suc- ance. Pathology cinate independently stimulates HSC ac- The liver is crucial for regulating the tivation. SUCNR1 signaling, therefore, Regulation of Lipolysis in White body’s metabolism by storing fuel mole- plays a role in HSC activation to restore Adipose Tissue cules such as glycogen and plays a major damaged tissue in the ischemic liver or In states of hypoglycemia, hormones role in lipid and amino acid conversion contributes to the formation of fibrosis. such as glucagon trigger adipocytes in or synthesis, as well as the degradation of The signaling pathways involved in white adipose tissue to degrade triglycer- toxic compounds. Likely, therefore, this this HSC activation remain obscure. In ides into free fatty acids for energy pro- organ is subject to multiple stressors pri- contrast to adipocytes or renal cells (see duction. Stimulatory Gs proteins medi- marily related to an unhealthy lifestyle. below), administration of succinate to ate this process of lipolysis. In SUCNR1ϩ In the liver, SUCNR1 is exclusively ex- HSCs fails to induce an intracellular adipocytes, succinate inhibits lipolysis in pressed in quiescent hepatic stellate cells Ca2ϩ response, nor does it decrease for- a pertussis toxin–dependent manner, (HSCs), but on activation of HSCs, the skolin-induced cAMP levels or increase showing that SUCNR1 signaling inhibits expression of SUCNR1 decreases rap- cAMP levels by itself.12 For comparison,

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the downstream effectors of SUCNR1 pared with controls.16 This suggests a downregulates SUCNR1 expression when signaling in different tissues and cell role for succinate in atherothrombosis, DCs achieve maturity. Furthermore, un- types are summarized in Table 1. in which succinate levels may increase derscoring the fact that the above observa- because of local hypoxia. tions are SUNCR1-mediated, mice chal- Apoptosis of Cardiomyocytes In hematopoietic progenitor cells, ac- lenged with tetanus toxin accumulate 14 A recent study by Aguiar et al. showed the tivated SUCNR1 signals through Gi/o higher levels of mature DCs in their lymph presence of mRNA encoding SUCNR1 and proteins to induce cell proliferation via nodes compared with SUCNR1Ϫ/Ϫ mice. protein in freshly isolated preparations of extracellular regulated kinases (ERK)1 Grafts from SUCNR1Ϫ/Ϫ mice show im- ventricular cardiomyocytes, where it local- and 2. Also, SUCNR1 activation protects proved outcome during skin graft rejec- izes in the sarcolemmal membrane and T- the erythroleukemic cell line, TF1, from se- tion.17 As such, interfering with SUCNR1 tubules. In these cardiomyocytes, succi- rum starvation-induced apoptosis. To- signaling by specific receptor antagonists nate leads to increased protein kinase A gether, this explains how administration of or preventing succinate accumulation may activity that subsequently releases intracel- succinate in a mouse model of chemother- be beneficial for patients receiving organ lular calcium transients. Moreover, succi- apy-induced myelosuppression leads to in- transplants. However, specific inhibitors of nate-stimulated cardiomyocytes show in- creased levels of hemoglobin, platelets, and the SUCNR1 remain to be developed. creased maximum peak height and higher neutrophils15; succinate therefore may be frequency of calcium transients, which af- beneficial to patients recovering from che- Vascularization of the Retina fect contraction of these cells. Importantly, motherapy. In the retina, SUCNR1 is predominantly prolonged incubation of cardiomyocytes In contrast, Rubic et al.17 did not detect expressed in the cell bodies of the retinal with succinate induces apoptosis, most mRNA encoding SUCNR1 in monocytes, ganglion cell layer.18 To study the role of likely caused by a combination of protein T cells, or B cells, but only in immature SUCNR1 in developing retina, siRNA kinase A activation and increased intracel- dendritic cells (DCs), suggesting that against mRNA encoding SUCNR1 was lular calcium levels or by the release of SUCNR1 expression is induced when injected into the eye of newborn rat prostaglandins and the subsequent trans- monocytes develop into immature DCs.17 pups, which decreases the vasculariza- activation of prostaglandin receptors.14 As In these cells, succinate stimulates migra- tion of the retina at day 4 postpartum such, SUCNR1 regulates apoptosis in the tion in a concentration-dependent man- compared with controls. In contrast, in- heart in states of ischemia and hypoxia. ner and thus mediates chemotaxis. More- jection of succinate increases vessel over, by phosphorylation of ERK1/2, numbers in the retina, clearly showing a Maturation and Sensitizing of SUCNCR1 and Toll-like receptors act in positive role for SUCNR1 in retinal Blood and Immune Cells synergy to potentiate the production of the vascularization. In addition, SUCNR1 Although not initially identified in tissue inflammatory cytokines TNF␣ and IL-1␤. regulates vessel growth through the panels,3,4 it is now evident that SUCNR1 On activation, immature DCs will mature production and release of proangio- is also expressed in hematopoietic pre- to antigen-presenting DCs that can subse- genic hormones. Moreover, the retinal cursor cells and multiple subtypes of quently activate T cells. Succinate treat- ganglion cells expressing SUCNR1 are blood and immune cells,15,16 as summa- ment of DCs promotes IFN␥ production essential for proper vascularization of rized in Table 1. When administered to of activated CD4ϩ T cells. the eye. However, in diabetes mellitus or platelets, succinate potentiates aggrega- The prostimulatory effects of succinate retinal ischemia, increased levels of suc- tion in a dose-dependent manner, in- on immature DCs are subject to a self- cinate induce high rates of neovascular- creasing maximum aggregation com- induced negative feedback loop, which ization, leading to retinopathy.17 In this

Table 1. Tissue distribution of SUCNR1 and its signaling effects in specific cell types Tissue Cell Type Effectors Reference ϩ Kidney HEK293 Ca2 , ERK1/2, prostaglandins 3 2ϩ Kidney Vascular endothelium, GENC Ca , NO, PGE2, renin release 11

Kidney Macula densa, MMDD1 p38, ERK1/2, COX-2, PGE2, renin release 20 2ϩ Kidney MDCK, collecting duct principal cells Ca , ERK1/2, PGE2, PGI2 19 Liver Hepatic Stellate cells ␣-SMA 12 ϩ Heart Cardiomyocytes PKA, Ca2 14 Bone marrow/Blood CD34 ϩ progenitor cells, megakaryocytes, IP, ERK1/2, proliferation, anti-apoptotic 15 erythroid progenitor cells Blood T cells, B cells, monocytes, platelets Potentiates platelet aggregation 16 ϩ Blood Immature dendritic cells Ca2 , chemotaxis, potentiates cytokine production 17 Retina Retinal ganglion neurons VEGF 18 White adipose Adipocytes Inhibition of lipolysis 4 ␣ ␣ ERK, extracellularly regulated kinase; PGE2, prostaglandin E2; COX-2, cyclooxygenase 2; PGI2, prostaglandin I2; -SMA, smooth-muscle actin; IP, inositol phosphate; VEGF, vascular endothelial growth factor.

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respect, inhibitors of SUCNR1 may pro- A vide a potential treatment.

REGULATION OF BP AND THE Glomerulus: RENIN-ANGIOTENSIN SYSTEM IN Vasodilation, PGE2 and NO cTAL: CD: THE DIABETIC KIDNEY + + release Na Na , H20 transport? transport? ERK1/2 activation Together with deorphanizing SUCNR1, He et al.3 observed that injection of suc- JGA: Renin release cinate in mice induces the release of renin from the juxtaglomerular appara- MD: tus (JGA) in the kidney, resulting in hy- PGE2 and NO pertension. Therefore, expression of release SUCNR1 may occur in the JGA, al- though this was not confirmed at the time. Since then, we and others deter- mined the localization of SUCNR1 in the kidney to establish its role in renal patho- physiology. The SUCNR1 localizes to the B renal vascular lumen, in particular the af- cTAL MD AA ferent arteriole and the glomerular vas- Renin culature. Moreover, SUCNR1 expresses on the luminal membrane of multiple PGE2 segments of the renal tubules: the cortical NO thick ascending limb (cTAL) of Henle’s loop, including the macula densa (MD), Mesangial and the cortical and medullary collecting cells duct (CD).11,19,20 The renal distribution of SUCNR1 and its proposed actions (see below) are summarized in Figure 3A. Recent work by the Peti-Peterdi group showed that SUCNR1 mediates Endothelial the release of renin from the JGA EA cells through SUCNR1 located in the vascu- lar luminal membrane11 or along the api- Figure 3. Localization of SUCNR1 and its signaling effect in the nephron. (A) This cal membrane of MD cells.19–21 Elegant schematic overview of the nephron shows the segments expressing SUCNR1 in dark gray: microperfusion studies combined with live glomerular vasculature, cTAL, MD, and CD. SUCNR1 activation in the AA and MD imaging of isolated glomeruli showed that induces the release of NO and PGE2, resulting in secretion of renin from the granular cells of the JGA, leading to activation of the renin-angiotensin system that affects AA width, perfusion with a succinate-containing BP, and renal sodium and water handling. Moreover, in cTAL and CD, SUCNR1 may also buffer induces renin release from the directly affect sodium and water reabsorption. Finally, SUCNR1 in the CD promotes granular cells of the JGA, which rapidly ERK1/2 phosphorylation, which may contribute to the development of diabetic nephrop- induce vasodilation of the afferent arte- athy. (B) SUCNR1 activation triggers the release of renin. SUCNR1 located in the luminal riole. This shows that SUCNR1 plays a membrane of MD cells, or in the plasma membrane of AA cells, induces the release of dynamic role in development of glomer- PGE2 and NO. This will promote the release of renin from the JGA granular cells. Glom, ular hyperfiltration and activation of the glomerular vasculature; AA, afferent arteriole; EA, efferent arteriole. renal renin-angiotensin system. The release of renin from the JGA is me- shown that activation of SUCNR1 on the Analogous to the development of hy- diated in part by the formation of NO. luminal membrane of MD cells triggers pertension on administration of succi- Moreover, activation of SUCNR1 in- renin release from the JGA through a sim- nate to mice,3 plasma levels of succinate creases levels of cyclooxygenase (COX)-2, ilar mechanism, although in this case, elevate in several rodent models of hy- leading to the production and release of SUCNR1 serves as a sensor for succinate in pertension and metabolic disease. Spon- 20 prostaglandin E2 that subsequently trans- tubular fluid rather than in blood. The taneous hypertensive rats, fatty Zucker activates EP2 and/or EP4 receptors on SUCNR1-mediated release of renin de- fa/fa rats, db/db diabetic mice, and ob/ob granular cells.11 Subsequently, it was scribed above is shown in Figure 3B. mice have two- to four-fold elevated suc-

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cinate levels compared with their nonhy- a role in diabetes and metabolic syn- Sustained tubular ERK1/2 phosphory- pertensive or lean controls.10 However, drome, the relationship between diabetes lation associates with proliferation of serum levels of succinate in hypertensive and development of hypertension was first tubular cells and the development of tu- Ϫ Ϫ or diabetic patients are similar to healthy suggested by work in SUCNR1 / mice. bulointerstitial fibrosis,29,30 and SUCNR1 age-matched controls.10 The source of The JGA and whole kidney renin content may be instrumental in the development of this discrepancy between rodent models of diabetic mice are elevated compared fibrosis in diabetic nephropathy and diabe- and patients remains unknown. with nondiabetic controls, and renin re- tes-induced hypertension.27 ERK1/2 phos- As SUCNR1 along the renal tubules lease is stimulated by perfusion of the af- phorylation downstream of SUCNR1 sense the availability of succinate, mea- ferent arteriole11 or the MD-containing activation in kidney cells is rapid and surements of succinate in excreted urine cTAL20 with a high glucose or succinate transient.19 Therefore, direct SUCNR1 sig- may provide an easy, noninvasive way to buffer. The observed release of renin naling, or by release of JGA renin and the determine SUCNR1 activity in kidney combined with the aforementioned dila- subsequent formation of angiotensin II, compared with circulating succinate lev- tion of the afferent arteriole resulting in may induce the tubular formation of (pro) els. Moreover, because of concentrating hyperfiltration are hallmarks of the dia- renin, as has recently been shown for the mechanisms along the nephron, the betic kidney. CD in diabetes31 and other tubular seg- more distal parts of the tubule may be In healthy individuals, the release of ments in hypertension.24,32–34 The released exposed to increased succinate levels renin from the JGA is subject to a nega- (pro)renin subsequently binds to its recep- compared with endothelial cells along tive feedback loop through angiotensin tor,34 leading to sustained ERK1/2 phos- the afferent arteriole that sense only cir- II, which activates its receptor on granu- phorylation.33 However, the exact role of culating and regional succinate. Indeed, lar cells to inhibit renin release by the SUCNR1 activation and mechanisms un- ϩ urinary succinate concentrations in dia- Ca2 -protein kinase C pathway.24 How- derlying these processes requires further betic mice are approximately 5 to 10 ever, in kidneys of diabetic mice, renin investigation. times higher than plasma succinate levels levels are increased, especially in the in mice with a similar genetic back- cortical areas around the JGA, where ground.10,11 In control mice, however, SUCNR1 is found,11,20 whereas no up- FUTURE PERSPECTIVES urinary succinate concentrations are regulation of renin is observed in Ϫ Ϫ similar to plasma levels,10,11 in which the SUCNR1 / mice. As such, SUCNR1 As shown above and summarized in concentrating effect of the nephron may may allow the body to escape from the Table 2, signaling through SUCNR1 is be partially counteracted by reabsorp- angiotensin II–negative feedback loop involved in the pathophysiology of dis- tion of succinate by a variety of dicar- and maintain high levels of (pro)renin, ease in multiple organs. These processes boxylate transporters along the proximal thereby contributing to sustained hyper- are linked particularly to local stress factors tubule.22 Recent studies also suggested tension.25–27 that affect the energy balance of a tissue, the SLCO4C1 transporter eliminates Nowadays, it is well established that such as ischemia, hypoxia, metabolic syn- uremic toxins, including succinate, and the production and release of renin is no drome, and diabetes mellitus; SUCNR1 upregulation of this transporter attenu- longer restricted to the JGA, and individ- senses local damage and increases inflam- ates hypertension and renal inflamma- ual components of the renin-angiotensin matory responses. Therefore, this recep- tion; statins stimulate this effect.23 Thus, system have been detected throughout tor acts a sensor of local stress that affects determination of the exact filtration frac- the nephron.28 The function of this para- cellular metabolism, as reflected by in- tion of succinate and the amount of suc- crine tubular renin-angiotensin system is creased formation and release of succi- cinate locally produced by tubular cells slowly emerging.24,26 In the kidney of di- nate. It is also clear that SUCNR1 is a reg- of the nephron awaits more specialized abetic mice, activation of SUCNR1 in ulator of BP in diabetes mellitus and may clearance studies. the cTAL20 and CD19 leads to increased contribute to the development of tubulo- Although these succinate measure- ERK1/2 phosphorylation, whereas this interstitial fibrosis in diabetic nephropa- ments indicate that SUCNR1 might play effect is absent in SUCNR1Ϫ/Ϫ mice. thy. Future challenges lie in elucidating the

Table 2. SUCNR1 in pathophysiology Tissue Model System SUCRN1 KO/ No SUCNR1 Stimulation Reference Kidney Diabetes mellitus BP not increased Renin release, hypertension 11,20 Liver (Ischemic) stress Stellate cell activation 12 Heart Ischemic stress Apoptosis 14 Blood Skin transplantation Improved graft survival Chemotaxis ϩ maturation of dendritic cells 17 Blood Chemotherapy Improved blood cell recovery 15 Retina Development Reduced vascularization, vascular density Accelerated retinal vascularization 18 Retina Ischemic stress Reduced retinopathy Angiogenesis, retinopathy 18 KO, knockout.

1420 Journal of the American Society of Nephrology J Am Soc Nephrol 22: 1416–1422, 2011 www.jasn.org BRIEF REVIEW cellular and molecular mechanisms re- Program (HEALTH-F2-2007-201590, enti- crine signal for liver damage. J Hepatol 47: sponsible for these effects and identifying tled EUNEFRON). J.H.R. is supported by the 262–269, 2007 13. De Minicis S, Seki E, Uchinami H, Kluwe J, Dutch Kidney Foundation (KJPB 09.012). specific receptor antagonists to prevent or Zhang Y, Brenner DA, Schwabe RF: Gene ameliorate this pathophysiology. expression profiles during hepatic stellate Besides the SUCNR1 found in the cell activation in culture and in vivo. Gastro- kidney, itspresence on immune cells could enterology 132: 1937–1946, 2007 DISCLOSURES also affect renal pathology. Succinate’s role 14. Aguiar CJ, Andrade VL, Gomes ER, Alves None. 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Nat Med 14: 1067–1076, 2008 subtle or redundant, and extracellular tion by anaerobic metabolism of citric acid 19. Robben JH, Fenton RA, Vargas SL, Schweer H, Peti-Peterdi J, Deen PM, Milligan G: Lo- succinate acts exclusively as a stress or cycle intermediates. Proc Natl Acad Sci USA 97: 2826–2831, 2000 calization of the succinate receptor in the damage signal, as we have shown here. Al- 8. Hems DA, Brosnan JT: Effects of ischaemia distal nephron and its signaling in polarized though more details are needed, it is clear on content of metabolites in rat liver and MDCK cells. Kidney Int 76: 1258–1267, that SUCNCR1 is a highly promising drug kidney in vivo. Biochem J 120: 105, 1970 2009 target in a multitude of disorders. 9. Hochachka PW, Dressendorfer RH: Succi- 20. Vargas SL, Toma I, Kang JJ, Meer EJ, Peti- nate accumulation in man during exercise. 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