Renin-angiotensin-aldosterone axis

Abstract

Renin, an aspartyl protease, catalyses the initial and rate-limiting step of the renin-angiotensin cascade the cleavage of angiotensin I from angiotensinogen. Although the central role of renin in cardiovascular homeostasis was appreciated long before the cloning of its cDNA and gene, the application of molecular techniques over the last decade has led to several advances in our understanding of its structure and functions. Important insights have been gained regarding the substrate specificity of renin (which has facilitated the development of clinically useful renin inhibitors), the transcriptional and translational regulation of renin production, and the nature of prorenin. The renin locus has been implicated as one of the determinants of hypertension in rodent models of genetic hypertension. Finally, the abilty to directly detect renin gene expression has provided a crucial means of determining the existence of and investigating the regulation and functions of tissue renin-angiotensin systems. The talk will focus on these novel aspects of the biology of renin.S 24 Angiotensin I-converting enzyme: New questions from recent structure/function studies. P. Corvol INSERM U36 -Collège de France -3, rue d'Ulm -75005 PARIS -FRANCE The molecular cloning of the somatic and germinal forms of angiotensin Iconverting enzyme (ACE) and recent structure/function studies have radically modified our knowledge of the structure, biosynthesis and expression of ACE and raised new important questions. Three questions will be discussed:1) The somatic enzyme contains two domains (N and C domains) which are both catalytically active and able to bind ACE inhibitors. However, it is not yet known whether each active site displays a distinct substrate specificity, even though the and C domains have a different chloride concentration requirement for catalytic activity and the domain a preference for the cleavage between Trp3 and Ser4 of LH-RH.2) ACE is anchored via its C-terminus by an -helix and can be solubilized by a proteolytic cleavage. However, the cellular localization, the identification of this putative proteolytic enzyme and the exact site(s) of ACE cleavages are unknown.3) Serum ACE (SACE) levels are genetically determined. A polymorphism of the ACE gene (VD) accounts for 47 % of the total SACE variance. There is a strong association between ACE gene polymorphism and the levels of SACE. This I/D polymorphism has been recently shown to be an independent risk factor in myocardial infarction in an epidemiological study. It remains to identify the ACE gene variant responsible for the genetic variation of SACE and putatively for increased ACE gene expression in tissues of the DD patients.