Abstract
The discovery of angiotensin-converting enzyme (ACE) 2 adds a new level of complexity to the understanding of the renin-angiotensin system. The high catalytic efficiency of ACE2 for the generation of angiotensin (ANG)-1-7 from ANG II suggests an important role of ACE2 in preventing ANG II accumulation, while at the same time enhancing ANG-1-7 formation. ACE and ACE2 may have counterbalancing functions and a regulatory role in fine-tuning the rate at which ANG peptides are formed and degraded. By counterregulating the actions of ACE on ANG II formation, ACE2 may play a role in maintaining a balanced status of the renninangiotensin system. This review focuses on the function of ACE2 and its possible roles in kidney disease and hypertension. Studies using models of ACE2 ablation and the pharmacologic administration of an ACE2 inhibitor suggest that decreased ACE2 activity alone or in combination with increased ACE activity may play a role in both diseases.
Keywords: Ace2 Gene, Glomerular Injury, Ace2 Gene Polymorphism, Ace2 Knockout Mouse
References and Recommended Reading
- 1.Tipnis S.R., Hooper N.M., Hyde R., et al. A human homolog of angiotensin-converting enzyme. Cloning and functional expression as a captopril-insensitive carboxypeptidase. J Biol Chem. 2000;274:33238–33243. doi: 10.1074/jbc.M002615200. [DOI] [PubMed] [Google Scholar]
- 2.Donoghue M., Hsieh F., Baronas E., et al. A novel angiotensin-coverting enzyme-related carboxypeptidase (ACE2) converts antiogensin I to angiotensin 1–9. Circ Res. 2000;87:E1–E9. doi: 10.1161/01.res.87.5.e1. [DOI] [PubMed] [Google Scholar]
- 3.Towler P., Staker B., Prasad S.G., et al. ACE2 X-ray structures reveal a large hinge-bending motion important for inhibitor binding and catalysis. J Biol Chem. 2004;279:17996–18007. doi: 10.1074/jbc.M311191200. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Guy J.L., Jackson R.M., Acharya K.R., et al. Angiotensin-converting enzyme-2 (ACE2): comparative modeling of the active site, specificity requirements, and chloride dependence. Biochemistry. 2003;42:13185–13192. doi: 10.1021/bi035268s. [DOI] [PubMed] [Google Scholar]
- 5.Zhang H., Wada J., Hida K., et al. Collectrin, a collecting duct-specific transmembrane glycoprotein, is a novel homolog of ACE2 and is developmentally regulated in embryonic kidneys. J Biol Chem. 2001;276:17132–17139. doi: 10.1074/jbc.M006723200. [DOI] [PubMed] [Google Scholar]
- 6.Danilczyk U., Sarao R., Remy C., et al. Essential role for collectrin in renal amino acid transport. Nature. 2006;444:1088–1091. doi: 10.1038/nature05475. [DOI] [PubMed] [Google Scholar]
- 7.Malakauskas S.M., Quan H., Fields T.A., et al. Aminoaciduria and altered renal expression of luminal amino acid transporters in mice lacking novel gene collectrin. Am J Physiol Renal Physiol. 2007;292:F533–F544. doi: 10.1152/ajprenal.00325.2006. [DOI] [PubMed] [Google Scholar]
- 8.Zhang Y., Wada J., Yasuhara A., et al. The role for HNF-1beta-targeted collectrin in maintenance of primary cilia and cell polarity in collecting duct cells. PLoS ONE. 2007;2:e414. doi: 10.1371/journal.pone.0000414. [DOI] [PMC free article] [PubMed] [Google Scholar] [Retracted]
- 9.Rella M., Elliot J.L., Revett T.J., et al. Identification and characterisation of the angiotensin converting enzyme-3 (ACE3) gene: a novel mammalian homologue of ACE. BMC Genomics. 2007;8:194. doi: 10.1186/1471-2164-8-194. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Danilczyk U., Penninger J.M. Angiotensin-converting enzyme II in the heart and the kidney. Circ Res. 2006;98:463–471. doi: 10.1161/01.RES.0000205761.22353.5f. [DOI] [PubMed] [Google Scholar]
- 11.Kuba K., Imai Y., Rao S., et al. A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury. Nat Med. 2005;11:875–879. doi: 10.1038/nm1267. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Imai Y., Kuba K., Rao S., et al. Angiotensin-converting enzyme 2 protects from severe acute lung failure. Nature. 2005;436:112–116. doi: 10.1038/nature03712. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Ye M., Wysocki J., Naaz P., et al. Increased ACE2 and decreased ACE protein in renal tubules from diabetic mice: a renoprotective combination? Hypertension. 2004;43:1120–1125. doi: 10.1161/01.HYP.0000126192.27644.76. [DOI] [PubMed] [Google Scholar]
- 14.Soler M.J., Wysocki J., Ye M., et al. ACE2 inhibition worsens glomerular injury in association with increased ACE expression in streptozotocin-induced diabetic mice. Kidney Int. 2007;72:614–623. doi: 10.1038/sj.ki.5002373. [DOI] [PubMed] [Google Scholar]
- 15.Ye M., Wysocki J., William J., et al. Glomerular localization and expression of angiotensin-converting enzyme 2 and angiotensin-converting enzyme: implications for albuminuria in diabetes. J Am Soc Nephrol. 2006;17:3067–3075. doi: 10.1681/ASN.2006050423. [DOI] [PubMed] [Google Scholar]
- 16.Wysocki J., Ye M., Soler M.J., et al. ACE and ACE2 activity in diabetic mice. Diabetes. 2006;55:2132–2139. doi: 10.2337/db06-0033. [DOI] [PubMed] [Google Scholar]
- 17.Vickers C., Hales P., Kaushik V., et al. Hydrolysis of biological peptides by human angiotensin-converting enzyme-related carboxypeptidase. J Biol Chem. 2002;277:14838–14843. doi: 10.1074/jbc.M200581200. [DOI] [PubMed] [Google Scholar]
- 18.Su Z., Zimpelmann J., Burns K.D. Angiotensin-(1–7) inhibits angiotensin II-stimulated phosphorylation of MAP kinases in proximal tubular cells. Kidney Int. 2006;69:2212–2218. doi: 10.1038/sj.ki.5001509. [DOI] [PubMed] [Google Scholar]
- 19.Ferrario C.M., Jessup J., Gallagher P.E., et al. Effects of renin-angiotensin system blockade on renal angiotensin-(1–7) forming enzymes and receptors. Kidney Int. 2005;68:2189–2196. doi: 10.1111/j.1523-1755.2005.00675.x. [DOI] [PubMed] [Google Scholar]
- 20.Elased K.M., Cunha T.S., Gurley S.B., et al. New mass spectrometric assay for angiotensin-converting enzyme 2 activity. Hypertension. 2006;47:1010–1017. doi: 10.1161/01.HYP.0000215588.38536.30. [DOI] [PubMed] [Google Scholar]
- 21.Shaltout H.A., Westwood B.M., Averill D.B., et al. Angiotensin metabolism in renal proximal tubules, urine, and serum of sheep: evidence for ACE2-dependent processing of angiotensin II. Am J Physiol Renal Physiol. 2007;292:F82–F91. doi: 10.1152/ajprenal.00139.2006. [DOI] [PubMed] [Google Scholar]
- 22.Li N., Zimpelmann J., Cheng K., et al. The role of angiotensin converting enzyme 2 in the generation of angiotensin 1–7 by rat proximal tubules. Am J Physiol Renal Physiol. 2005;288:F353–F362. doi: 10.1152/ajprenal.00144.2004. [DOI] [PubMed] [Google Scholar]
- 23.Ocaranza M.P., Godoy I., Jalil J.E., et al. Enalapril attenuates downregulation of angiotensin-converting enzyme 2 in the late phase of ventricular dysfunction in myocardial infarcted rat. Hypertension. 2006;48:572–578. doi: 10.1161/01.HYP.0000237862.94083.45. [DOI] [PubMed] [Google Scholar]
- 24.Ferrario C.M., Jessup J., Chappell M.C., et al. Effect of angiotensin-converting enzyme inhibition and angiotensin II receptor blockers on cardiac angiotensin-converting enzyme 2. Circulation. 2005;111:2605–2610. doi: 10.1161/CIRCULATIONAHA.104.510461. [DOI] [PubMed] [Google Scholar]
- 25.Burrell L.M., Risvanis J., Kubota E., et al. Myocardial infarction increases ACE2 expression in rat and humans. Eur Heart J. 2005;26:369–375. doi: 10.1093/eurheartj/ehi114. [DOI] [PubMed] [Google Scholar]
- 26.Donoghue M., Wakimoto H., Maguire C.T., et al. Heart block, ventricular tachycardia, and sudden death in ACE2 transgenic mice with downregulated connexins. J Mol Cell Cardiol. 2003;35:1043–1053. doi: 10.1016/S0022-2828(03)00177-9. [DOI] [PubMed] [Google Scholar]
- 27.Douglas G.C., O’Bryan M.K., Hedger M.P., et al. The novel angiotensin-converting enzyme (ACE) homolog, ACE2, is selectively expressed by adult Leydig cells of the testis. Endocrinology. 2004;145:4703–4711. doi: 10.1210/en.2004-0443. [DOI] [PubMed] [Google Scholar]
- 28.Huang L., Sexton D.J., Skogerson K., et al. Novel peptide inhibitors of angiotensin-converting enzyme 2. J Biol Chem. 2003;278:15532–15540. doi: 10.1074/jbc.M212934200. [DOI] [PubMed] [Google Scholar]
- 29.Riviere G., Michaud A., Breton C., et al. Angiotensin-converting enzyme 2 (ACE2) and ACE activities display tissue-specific sensitivity to undernutrition-programmed hypertension in the adult rat. Hypertension. 2005;46:1169–1174. doi: 10.1161/01.HYP.0000185148.27901.fe. [DOI] [PubMed] [Google Scholar]
- 30.Rice G.I., Jones A.L., Grant P.J., et al. Circulating activities of angiotensin-converting enzyme, its homolog, angiotensinconverting enzyme 2, and neprilysin in a family study. Hypertension. 2006;48:914–920. doi: 10.1161/01.HYP.0000244543.91937.79. [DOI] [PubMed] [Google Scholar]
- 31.Lambert D.W., Yarski M., Warner F.J., et al. Tumor necrosis factor-alpha convertase (ADAM17) mediates regulated ectodomain shedding of the severe-acute respiratory syndrome-coronavirus (SARS-CoV) receptor, angiotensin-converting enzyme-2 (ACE2) J Biol Chem. 2005;280:30313–30319. doi: 10.1074/jbc.M505111200. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32.Warner F.J., Lew R.A., Smith A.I., et al. Angiotensin-converting enzyme 2 (ACE2), but not ACE, is preferentially localized to the apical surface of polarized kidney cells. J Biol Chem. 2005;280:39353–39362. doi: 10.1074/jbc.M508914200. [DOI] [PubMed] [Google Scholar]
- 33.Tikellis C., Johnston C.I., Forbes J.M., et al. Characterization of renal angiotensin-converting enzyme 2 in diabetic nephropathy. Hypertension. 2003;41:392–397. doi: 10.1161/01.HYP.0000060689.38912.CB. [DOI] [PubMed] [Google Scholar]
- 34.Brosnihan K.B., Neves L.A., Joyner J., et al. Enhanced renal immunocytochemical expression of ANG-(1-7) and ACE2 during pregnancy. Hypertension. 2003;42:749–753. doi: 10.1161/01.HYP.0000085220.53285.11. [DOI] [PubMed] [Google Scholar]
- 35.Lely A.T., Hamming I., van Goor H., Navis G.J. Renal ACE2 expression in human kidney disease? J Pathol. 2004;204:587–593. doi: 10.1002/path.1670. [DOI] [PubMed] [Google Scholar]
- 36.Wysocki J, Soler MJ, Ye M, Batlle D. ACE2 is critically important for angiotensin II metabolism in podocytes. J Am Soc Nephrol. 2006;17:TH–PO877. [Google Scholar]
- 37.Velez J.C., Bland A.M., Arthur J.M., et al. Characterization of renin-angiotensin system enzyme activities in cultured mouse podocytes. Am J Phsiol Renal Physiol. 2007;293:F398–F407. doi: 10.1152/ajprenal.00050.2007. [DOI] [PubMed] [Google Scholar]
- 38.Hamming I., Cooper M.E., Haagmans B.L., et al. The emerging role of ACE2 in physiology and disease. J Pathol. 2007;212:1–11. doi: 10.1002/path.2162. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 39.Oudit G.Y., Herzenberg A.M., Kassiri Z., et al. Loss of angiotensin-converting enzyme-2 leads to the late development of angiotensin II-dependent glomerulosclerosis. Am J Pathol. 2006;168:1808–1820. doi: 10.2353/ajpath.2006.051091. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 40.Wong D.W., Oudit G.Y., Reich H., et al. Loss of angiotensin-converting enzyme-2 (Ace2) accelerates diabetic kidney injury. Am J Pathol. 2007;171:438–451. doi: 10.2353/ajpath.2007.060977. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 41.Crackower M.A., Sarao R., Oudit G.Y., et al. Angiotensin-converting enzyme 2 is an essential regulator of heart function. Nature. 2002;417:822–828. doi: 10.1038/nature00786. [DOI] [PubMed] [Google Scholar]
- 42.Tikellis C., Cooper M.E., Bialkowski K., et al. Developmental expression of ACE2 in the SHR kidney: a role in hypertension? Kidney Int. 2006;70:34–41. doi: 10.1038/sj.ki.5000428. [DOI] [PubMed] [Google Scholar]
- 43.Zhong J., Yan Z., Liu D., et al. Association of angiotensin-converting enzyme 2 gene A/G polymorphism and elevated blood pressure in Chinese patients with metabolic syndrome. J Lab Clin Med. 2006;147:91–95. doi: 10.1016/j.lab.2005.10.001. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 44.Huang W., Yang W., Wang Y., et al. Association study of angiotensin-converting enzyme 2 gene (ACE2) polymorphisms and essential hypertension in northern Han Chinese. J Hum Hypertens. 2006;20:968–971. doi: 10.1038/sj.jhh.1002090. [DOI] [PubMed] [Google Scholar]
- 45.Fan X., Wang Y., Sun K., et al. Polymorphisms of ACE2 gene are associated with essential hypertension and antihypertensive effects of Captopril in women. Clin Pharmacol Ther. 2007;82:187–196. doi: 10.1038/sj.clpt.6100214. [DOI] [PubMed] [Google Scholar]
- 46.Benjafield A.V., Wang W.Y., Morris B.J. No association of angiotensin-converting enzyme 2 gene (ACE2) polymorphisms with essential hypertension. Am J Hypertens. 2004;17:624–628. doi: 10.1016/j.amjhyper.2004.02.022. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 47.Lieb W., Graf J., Götz A., et al. Association of angiotensin-converting enzyme 2 (ACE2) gene polymorphisms with parameters of left ventricular hypertrophy in men. Results of the MONICA Augsburg echocardiographic substudy. J Mol Med. 2006;84:88–96. doi: 10.1007/s00109-005-0718-5. [DOI] [PubMed] [Google Scholar]
- 48.Wakahara S., Konoshita T., Mizuno S., et al. Synergistic expression of angiotensin-converting enzyme (ACE) and ACE2 in human renal tissue and confounding effects of hypertension on the ACE to ACE2 ratio. Endocrinology. 2007;148:2453–2457. doi: 10.1210/en.2006-1287. [DOI] [PubMed] [Google Scholar]
- 49.Joyner J., Neves L.A., Granger J.P., et al. Temporal-spatial expression of ANG-(1-7) and angiotensin-converting enzyme 2 in the kidney of normal and hypertensive pregnant rats. Am J Physiol Regul Integr Comp Physiol. 2007;293:R169–R177. doi: 10.1152/ajpregu.00387.2006. [DOI] [PubMed] [Google Scholar]
- 50.Gurley S.B., Allred A., Le T.H., et al. Altered blood pressure responses and normal cardiac phenotype in ACE2-null mice. J Clin Invest. 2006;116:2218–2225. doi: 10.1172/JCI16980. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 51.Ye M., Wysocki J., Rodriguez E., et al. Recombinant ACE2 attenuates angiotensin II induced hypertension. Hypertension. 2007;50:LB10. [Google Scholar]
