BRIEF REVIEW www.jasn.org 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, J Am Soc Nephrol 22: 1416–1422, 2011 Clinical Potential of SUCNR1 1417 BRIEF REVIEW www.jasn.org 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.