Intracrine renin and angiotensin II: a novel role in cardiovascular and renal cellular regulation

Abstract

Since renin was discovered by Robert Tigerstedt more than a century ago, interest in the renin–angiotensin system (RAS) remains stronger than ever [1]. Tigerstedt injected saline extracts prepared from a rabbit kidney into other rabbits and observed marked increases in arterial blood pressure, which led to the hypothesis that the kidney might release an endocrine substance to control systemic blood pressure [1]. This pressor substance was named renin by Tigerstedt. It was Harry Goldblatt who confirmed and extended Tigerstedt’s discovery of the RAS in his legendary studies on two-kidney, one-clip renal hypertension in 1934 [2]. For several decades, angiotensin II was known as an endocrine peptide that is formed by the actions of kidney-derived renin and lung-derived angiotensin-converting enzyme (ACE) and causes systemic hypertension. The RAS is now well recognized as a dual vasoactive system, acting as both a circulating endocrine system and a local tissue paracrine/autocrine system [3,4]. Re further defined intracrine angiotensin II as the effector peptide that is either synthesized within a cell via interactions of renin, angiotensinogen and ACE or internalized from extracellular angiotensin II [5]. Most or all major components of the RAS cascade, including angiotensinogen, renin, ACE and angiotensin II receptors (AT1 or AT2), have been demonstrated in the heart, adrenal glands, brain and blood vessels [6,7]. Renin, the rate-limiting enzyme in the cascade, acts on the hepatocyte-synthesized substrate angiotensinogen to form angiotensin I, which is converted to angiotensin II by ACE. Angiotensin II is further metabolized by aminopeptidases into the active fragments angiotensin III and/or angiotensin IV. The principal effector molecule of the RAS cascade is angiotensin II, although other angiotensin fragments such as angiotensin III, angiotensin 1–7 and angiotensin IV have been shown to be biologically active [6]. The presence of renin, angiotensinogen and ACE in many tissues makes local formation of angiotensin II possible, whereas expression of angiotensin II receptors is essential for angiotensin II to induce biological effects at target sites. Two major classes of angiotensin II receptors are expressed in the heart, kidney, brain, adrenals and blood vessels, AT1 and AT2 [6,7]. AT1 is a G protein-coupled receptor belonging to the superfamily of seven transmembrane-spanning proteins. Two subtypes of AT1, designated AT1A and AT1B, have been identified in rodents, but the former is the predominant isoform in the kidney, blood vessels, and heart [6]. Although the pressor effect of angiotensin II is historically considered its primary action, it also stimulates aldosterone synthesis, promotes body salt and fluid retention, and induces cellular growth and proliferation in cardiovascular and renal tissues [4,6]. Most of the known actions of angiotensin II are mediated by the AT1 receptor, which is coupled to multiple signaling pathways, including phospholipase C, D, and A2 signaling, mitogen-activated protein kinase, and tyrosine kinase. Activation of AT1 leads to phosphoinositide hydrolysis, mobilization of intracellular calcium, and inhibition of adenylate cyclase [6–8].