Renin, prorenin, and the direct renin inhibitor aliskiren
Authors:
Adolf Slabý; Aleš Žák
Authors‘ workplace:
Univerzita Karlova v Praze, 1. lékařská fakulta, IV. interní klinika VFN
Published in:
Čas. Lék. čes. 2010; 149: 55-60
Category:
Review Article
Overview
The renin-angiotensin system plays an important role in various physiological and pathophysiological regulatory mechanisms. Within the past few years, the classical concept of a linear enzymatic cascade has experienced substantial changes. A parallel counter-regulatory axis has been identified which involves the angiotensin converting enzyme homologue ACE2, angiotensin (1–7), and receptors Mas. The research in prorenin and its non-proteolytic activation has greatly advanced after the discovery of cellular receptors (P)RR; binding of renin or prorenin to these receptors not only facilitates angiotensin generation, but at the same time activates specific signal transduction pathways. The long-term search for clinically useful direct renin inhibitors has recently succeeded with the new antihypertensive drug aliskiren. While beneficial effects of aliskiren on some markers of cardiovascular and renal diseases have been proved in large clinical studies, important questions remain to be solved.
Key words:
renin-angiotensin system, ACE2 – angiotensin (1–7) – receptors Mas axis, nonproteolytic activation of prorenin, receptors (P)RR, direct renin inhibitor aliskiren.
Sources
1. Horký K. Systém renin-angiotenzin a arteriální hypertenze. In: Marek J, et al. Endokrinní hypertenze. Praha: Galén 2004; 3–45.
2. Slabý A, et al. Aktivita reninu a angiotensináz v krvi z ledvinové žíly po podání angiotensinu. Čas Lék čes 1967; 106: 232–236.
3. Chappell MC. Emerging evidence for a functional angiotensin-converting enzyme 2 – angiotensin-(1–7) – Mas receptor axis: More than regulation of blood pressure? Hypertension 2007; 50: 596–599.
4. Santos RAS, et al. Recent advances in the angiotensin-converting enzyme 2 – angiotensin(1–7) – Mas axis. Exp Physiol 2008; 93: 519–527.
5. Tipnis SR, et al. A human homolog of angiotensin-converting enzyme. Cloning and functional expression as a captopril-insensitive carboxypeptidase. J Biol Chem 2000; 275: 33238–33243.
6. Donoghue M, et al. A novel angiotensin-converting enzyme-related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1–9. Circ Res 2000; 87: E1–E9.
7. Lieb W, et al. Association of angiotensin-converting enzyme 2 (ACE2) gene polymorphism with parameters of left ventricular hypertrophy in men. Results of the MONICA Augsburg echocardiographic study. J Mol Med 2006; 84: 88–96.
8. Santos RAS, et al. Expression of an angiotensin-(1–7)-producing fusion protein produces cardioprotective effects in rats. Physiol Genomics 2004; 17: 292–299.
9. Averill DB, et al. Cardiac angiotensin-(1–7) in ischemic cardiomyopathy. Circulation 2003; 106: 2141–2146.
10. Campagnole-Santos MJ, et al. Cardiovascular effects of angiotensin-(1-7) injected into the dorsal medulla of rats. Am J Physiol 1989; 257: H324–H329.
11. Langeveld B, et al. Angiotensin-(1–7) attenuates neointimal formation after stent implantation in the rat. Hypertension 2005; 45: 1–4.
12. Su Z, et al. Angiotensin-(1–7) inhibits angiotensin II-stimulated phosphorylation of MAP kinases in proximal tubular cells. Kidney Int 2006; 69: 2212–2218.
13. Allred AJ, et al. Pathways for angiotensin-(1-7) metabolism in pulmonary and renal tissues. Am J Physiol Renal Physiol 2000; 279: F841–F850.
14. Kostenis E, et al. G-protein-coupled receptor Mas is a physiological antagonist of the angiotensin II type 1 receptor. Circulation 2005; 111: 1806–1813.
15. Soler MJ, et al. Pharmacologic modulation of ACE2 expression. Curr Hypertens Rep 2008; 10: 410–440.
16. Ferreira AJ, et al. The nonpeptide angiotensin-(1–7) receptor Mas agonist AVE 0991 attenuates heart failure induced by myocardial infarction. Am J Physiol Heart Circ Physiol 2007; 292: H1113–H1119.
17. Schweda F, et al. Renin release. Physiology 2007; 22: 310–319.
18. Krop M, et al. Circulating versus tissue renin-angiotensin system: On the origin of (pro)renin. Curr Hypertens Rep 2008; 10: 112–118.
19. Krop M, et al. Renin and prorenin disappearance in humans post-nephrectomy: Evidence of binding? Front Biosci 2008; 13: 3931–3939.
20. Deinum J, et al. Increase in serum prorenin precedes onset of microalbuminuria in patients with insulin-dependent diabetes mellitus. Diabetologie 1999; 42: 1006–1010.
21. Derkx FH, et al. Nonproteolytic “activation“ of prorenin by active site-directed renin inhibitors as demonstrated by renin-specific monoclonal antibody. J Biol Chem 1992; 267: 22837–22842.
22. Suzuki F, et al. Human prorenin has “gate and handle“ regions for its non–proteolytic activation. J Biol Chem 2003; 278: 22217–22222.
23. Ichikara A, et al. Inhibition of diabetic nephropathy by a decoy peptide corresponding to the “handle“ region for nonproteolytic activation of prorenin. J Clin Invest 2004; 114: 1128–1135.
24. Ichikara A, et al. Nonproteolytic activation of prorenin contributes to development of cardiac fibrosis in genetic hypertension. Hypertension 2006; 47: 894–900.
25. Danser AHJ, et al. Spotlight on renin: The Renin Academy Summit: Advancing the understanding of renin science. J Renin Angiotensin Aldosterone Syst 2008; 9: 119–122.
26. Nguyen G, et al. Pivotal role of the renin/prorenin receptor in angiotensin II production and cellular responses to renin. J Clin Invest 2002; 109: 1417–1427.
27. Nguyen G, et al. Prorenin and (pro)renin receptor: A review of available data from in vitro studies and experimental models in rodents. Exp Physiol 2008; 93: 557–563.
28. Bader M. Spotlight on renin: The second life of the (pro)renin receptor. J Renin Angiotensin Aldosterone Syst 2007; 8: 205–208.
29. Campbell DJ. Critical review of prorenin and (pro)renin receptor research. Hypertension 2008; 51: 1259–1264.
30. Schefe JH, et al. A novel signal transduction cascade involving direct physical interaction of the renin/prorenin receptor with the transcription factor promyelocytic zinc finger protein. Circulation Res 2006; 99: 1355–1366.
31. He M, et al. Inhibition of renin/prorenin receptor attenuated mesangial cell proliferation and reduced associated fibrotic factor release. Eur J Pharmacol 2009; 606: 155–161.
32. Ichihara A, et al. Drug discovery for overcoming chronic kidney disease (CKD): New therapy for CKD by a (pro)renin-receptor-blocking decoy peptide. J Pharmacol Sci 2009; 109: 20–23.
33. Danser AHJ. (Pro)renin receptors: Are they biologically relevant? Curr Opin Nephrol Hypertens 2009; 18: 74–78.
34. Bühler FR, et al. Propranolol inhibition of renin secretion: A specific approach to diagnosis and treatment of renin-dependent hypertensive diseases. N Engl J Med 1972; 287: 1209–1214.
35. Slabý A, et al. Beta-adrenergic blockade and plasma renin activity in borderline hypertension. Eur J Clin Pharmacol 1973; 6: 145–149.
36. Yoneda T, et al. Aldosterone breakthrough during angiotensin II receptor blockade in hypertensive patients with diabetes mellitus. Am J Hypertens 2007; 20: 1329–1333.
37. Staessen JA, et al. Oral renin inhibitors. Lancet 2006; 368: 1449–1456.
38. Wood JM, et al. Structure-based design of aliskiren, a novel orally effective renin inhibitor. Biochem Biophys Res Commun 2003; 308: 698–705.
39. Nussberger J, et al. Angiotensin II suppression in humans by the orally active renin inhibitor aliskiren: Comparison with enalapril. Hypertension 2002; 39: e1–e8.
40. Azizi M, et al. Hormonal and hemodynamic effects of aliskiren and valsartan and their combination in sodium-replete normotensive individuals. Clin J Am Soc Nephrol 2007; 2: 947–955.
41. Nussberger J, et al. Plasma renin and the antihypertensive effect of the orally active renin inhibitor aliskiren in clinical hypertension. Int J Clin Pract 2007; 61: 1461–1468.
42. Sealey JE, et al. Aliskiren, the first renin inhibitor for treating hypertension: Reactive renin secretion may limit its effectiveness. Am J Hypertens 2007; 20: 389–391.
43. Danser AHJ, et al. The renin rise with aliskiren: It’s simply stoichiometry. Hypertension 2008; 51: e27–e28.
44. Schefe JH, et al. Prorenin engages the (pro)renin receptor like renin and both ligand activities are unopposed by aliskiren. J Hypertens 2008; 26: 1787–1795.
45. Feldt S, et al. Prorenin and renin-induced extracellular signal-regulated kinase 1/2 activation in monocytes is not blocked by aliskiren or the handle-region peptide. Hypertension 2008; 51: 682–688.
46. Feldman DL, et al. Effects of aliskiren on blood pressure, albuminuria, and (pro)renin receptor expression in diabetic TG (mRen-2)27 rats. Hypertension 2008; 52: 130–136.
47. Campbell DC. Interpretation of plasma renin concentration in patients receiving aliskiren therapy. Hypertension 2008; 51: 15–18.
48. Batenburg WW, et al. Prorenin and the (pro)renin receptor: Binding kinetics, signalling and interaction with aliskiren. J Renin Angiotensin Aldosterone Syst 2008; 9: 181–184.
49. Batenburg WW, et al. Aliskiren-binding increases half life of renin and prorenin in rat aortic vascular smooth muscle cells. Arterioscler Thromb Vasc Biol 2008; 28: 1151–1157.
50. Imanishi T, et al. Renin inhibitor aliskiren improves impaired nitric oxide bioavailability and protects against atherosclerotic changes. Hypertension 2008; 52: 563–572.
51. Habibi J, et al. Renin inhibition attenuates insulin resistance, oxidative stress, and pancreatic remodeling in the transgenic Ren2 rat. Endocrinology 2008; 149: 5643–5653.
52. Nussberger J, et al. Renin inhibition by aliskirene prevents atherosclerosis progression: Comparison with irbesartan, atenolol, and amlodipine. Hypertension 2008; 51: 1306–1311.
53. Sever PS, et al. Managing cardiovascular and renal risk: The potential of direct renin inhibition. J Renin Angiotensin Aldosterone Syst 2009; 10: 65–76.
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Journal of Czech Physicians
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