Review: Intrarenal angiotensin II levels in normal and hypertensive states (original) (raw)
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Expression of an angiotensin-(1-7)producing fusion protein produces cardioprotective effects in rats. ] is a recently described heptapeptide product of the renin-angiotensin system. Because biosynthesis of ANG-(1-7) increases in animals treated with cardioprotective drugs and inactivation of the gene for angiotensin converting enzyme 2 [an enzyme involved in the biosynthesis of ANG-(1-7)] leads to the development of cardiac dysfunction, it has been suggested that ANG-(1-7) has cardioprotective properties. To directly test this possibility, we have generated transgenic rats that chronically overproduce ANG-(1-7) by using a novel fusion protein methodology. TGR(A1-7)3292 rats show testicular-specific expression of a cytomegalovirus promoter-driven transgene, resulting in a doubling of circulating ANG-(1-7) compared with nontransgenic control rats. Radiotelemetry hemodynamic measurements showed that transgenic rats presented a small but significant increase in daily and nocturnal heart rate and a slight but significant increase in daily and nocturnal cardiac contractility estimated by dP/d t measurements. Strikingly, TGR(A1-7)3292 rats were significantly more resistant than control animals to induction of cardiac hypertrophy by isoproterenol. In addition, transgenic rats showed a reduced duration of reperfusion arrhythmias and an improved postischemic function in isolated Langendorff heart preparations. These results support a cardioprotective role for circulating ANG-(1-7) and provide a novel tool for evaluating the functional role of ANG-(1-7). engineered protein; renin-angiotensin system; heart hypertrophy THE HEPTAPEPTIDE angiotensin-(
Seldin and Giebisch's The Kidney, 2013
The concept of tissue renin-angiotensin systems (RAS) is now well established and it is now usual to think in terms of renal and tissue systems. At the same time it has emerged that angiotensin II (Ang II) is not the only biologically active peptide generated by the RAS. At least three others have been identified: the heptapeptide Ang III, the hexapeptide Ang IV and Ang 1-7. Specific receptors exits for the last two peptides. In addition, the range of possible physiological and pathophysiological properties for Ang II has been expanding. The current perception of the RAS is therefore that of a much more complex system than previously believed, with autocrine, paracrine and endocrine properties extending beyond the cardiovascular system. This mini-review focuses on the synthetic pathways of the Ang peptides and describes some of their pleiotropic actions.
Angiotensin-(1 7) Is a Modulator of the Human Renin-Angiotensin System
Hypertension, 1999
The renin-angiotensin system is important for cardiovascular homeostasis. Currently, therapies for different cardiovascular diseases are based on inhibition of angiotensin-converting enzyme (ACE) or angiotensin II receptor blockade. Inhibition of ACE blocks metabolism of angiotensin-(1-7) to angiotensin-(1-5) and can lead to elevation of angiotensin-(1-7) levels in plasma and tissue. In animal models, angiotensin-(1-7) itself causes or enhances vasodilation and inhibits vascular contractions to angiotensin II. The function of angiotensin-(1-5) is unknown. We investigated whether angiotensin-(1-7) and angiotensin-(1-5) inhibit ACE or antagonize angiotensin-induced vasoconstrictions in humans. ACE activity in plasma and atrial tissue was inhibited by angiotensin-(1-7) up to 100%, with an IC 50 of 3.0 and 4.0 mol/L, respectively. In human internal mammary arteries, contractions induced by angiotensin I and II and the non-ACE-specific substrate [Pro 11 ,D-Ala 12 ]-angiotensin I were antagonized by angiotensin-(1-7) (10 Ϫ5 mol/L) in a noncompetitive way, with a 60% inhibition of the maximal response to angiotensin II. Contractions to ACE-specific substrate [Pro 10 ]-angiotensin I were also inhibited, an effect only partly accounted for by antagonism of angiotensin II. Angiotensin-(1-5) inhibited plasma ACE activity with a potency equal to that of angiotensin I but had no effect on arterial contractions. In conclusion, angiotensin-(1-7) blocks angiotensin II-induced vasoconstriction and inhibits ACE in human cardiovascular tissues. Angiotensin-(1-5) only inhibits ACE. These results show that angiotensin-(1-7) may be an important modulator of the human renin-angiotensin system. (Hypertension. 1999;34:296-301.)
Clinical and Experimental Pharmacology and Physiology, 1990
I . Serum angiotensin converting enzyme activity (ACEA) and plasma renin activity ( P R A ) were determined in rats under different experimental conditions such as: nephrotic syndrome (NS), bilateral nephrectomy (BN), renovascular hypertension (RH), dehydration (DEH). anaesthesia (AN), low sodium diet (LSD) and high sodium diet (HSD), and injection with propranolol (PRO) and isoprenaline (ISO).
Physiology of Local Renin-Angiotensin Systems
Physiological Reviews, 2006
Since the first identification of renin by Tigerstedt and Bergmann in 1898, the renin-angiotensin system (RAS) has been extensively studied. The current view of the system is characterized by an increased complexity, as evidenced by the discovery of new functional components and pathways of the RAS. In recent years, the pathophysiological implications of the system have been the main focus of attention, and inhibitors of the RAS such as angiotensin-converting enzyme (ACE) inhibitors and angiotensin (ANG) II receptor blockers have become important clinical tools in the treatment of cardiovascular and renal diseases such as hypertension, heart failure, and diabetic nephropathy. Nevertheless, the tissue RAS also plays an important role in mediating diverse physiological functions. These focus not only on the classical actions of ANG on the cardiovascular system, namely, the maintenance of cardiovascular homeostasis, but also on other functions. Recently, the research efforts studying t...
Nephrology Dialysis Transplantation, 2005
The concept of tissue renin-angiotensin systems (RAS) is now well established and it is now usual to think in terms of renal and tissue systems. At the same time it has emerged that angiotensin II (Ang II) is not the only biologically active peptide generated by the RAS. At least three others have been identified: the heptapeptide Ang III, the hexapeptide Ang IV and Ang 1-7. Specific receptors exits for the last two peptides. In addition, the range of possible physiological and pathophysiological properties for Ang II has been expanding. The current perception of the RAS is therefore that of a much more complex system than previously believed, with autocrine, paracrine and endocrine properties extending beyond the cardiovascular system. This mini-review focuses on the synthetic pathways of the Ang peptides and describes some of their pleiotropic actions.
Enhancement of Collecting Duct Renin in Angiotensin II-Dependent Hypertensive Rats
Hypertension, 2004
Distal nephron renin may provide a possible pathway for angiotensin (Ang) I generation from proximally delivered angiotensinogen. To examine the effects of Ang II on distal nephron renin, we compared renin protein and mRNA expression in control and Ang II-infused rats. Kidneys from sham (n=9) and Ang II-infused (80 ng/kg per minute, 13 days, n=10) Sprague-Dawley rats were processed by immunohistochemistry, Western blot, reverse transcriptase-polymerase chain reaction (RT-PCR), and quantitative real-time RT-PCR. Ang II infusion increased systolic blood pressure (181±4 versus 115±5 mm Hg) and suppressed plasma and kidney cortex renin activity. Renin immunoreactivity was suppressed in juxtaglomerular apparatus (JGA) cells in Ang II-infused rats compared with sham (0.1±0.1 versus 1.0±0.1 relative ratio) but increased in distal nephron segments (6.4±1.4 versus 1.0±0.1 cortex; 2.5±0.3 versus 1.0±0.2 medulla). Tubular renin immunostaining was apically distributed in principal cells colocalizing with aquaporin-2 in connecting tubules and cortical and medullary collecting ducts. Renin protein levels were decreased in the kidney cortex of Ang II-infused rats compared with that of sham (0.4±0.2 versus 1.0±0.4) rats but higher in the kidney medulla (1.2±0.4 versus 1.0±0.1). In kidney medulla, RT-PCR and quantitative real-time PCR showed similar levels of renin transcript in both groups. In summary, the detection of renin mRNA in the renal medulla, which is devoid of JGA, indicates local synthesis rather than an uptake of JGA renin. In contrast to the inhibitory effect of Ang II on JGA renin, Ang II infusion stimulates renin protein expression in collecting ducts and maintains renin transcriptional levels in the medulla, which may contribute to the increased intrarenal Ang II levels in Ang IIdependent hypertension.
Contribution of the renin-angiotensin system to the control of intrarenal hemodynamics
Kidney International, 1984
Intensive investigative efforts probing the many characteristics and potential functions of the renin-angiotensin system (RAS) have resulted in an exponentially expanding literature. In this editorial, we focus on the renal hemodynamic influences exerted by the RAS as a local regulatory mechanism. Indeed, local control was one initial function ascribed to the RAS by early investigators in this area. Because of its unique structure, the juxtaglomerular apparatus, now known to be the major site of renin formation, intrigued morphologists. It was postulated that the cells of the juxtaglomerular apparatus could control blood flow through the glomerulus by swelling and shrinking the afferent arteriolar lumen [1]. The unique juxtaposition of the macula densa cells of the early distal tubule to the glomerular arterioles also suggested mechanisms linking the function of the tubules with that of the arterioles [2-4]. Goormaghtigh [5] proposed an endocrine function for the juxtaglomerular apparatus and demonstrated uncanny insight in postulating the release of an agent by this structure that could activate or form a vasoactive substance which, in turn, influenced local vascular tone. Although some investigators continued to support the notion that local control was a major function of the RAS [6-8], the major areas of investigation in this field were oriented toward non-renal functions of the system such as in the control of aldosterone release, the regulation of systemic cardiovascular function, and the pathophysiology of hypertension [9]. Recent investigations, however, have renewed enthusiasm regarding the possibility that locally formed angiotensin II (All) may participate as an important modulator of renal vascular tone.
Nephrology Dialysis Transplantation, 2013
A large body of evidence supports the presence of local production of angiotensins in the kidney. It is widely believed that renin-angiotensin system (RAS) blockers, through interference with such production and/or the local effects of angiotensin (Ang) II, exert protective renal effects. Yet, whether such production affects blood pressure independently from the circulating RAS is still a matter of debate. To investigate this, a recent study by Gonzalez-Villalobos et al. (J Clin Invest 2013; 123: 2011-2023 has studied the consequences of infusing Ang II or the nitric oxide synthase inhibitor L-NAME in mice lacking renal angiotensin-converting enzyme (ACE). They observed blunted blood pressure and renal responses in the renal ACE knockout mice versus wild-type controls. This review discusses to what degree these findings can be considered as unequivocal evidence for ACE-mediated Ang II formation in the kidney as an independent determinant of hypertension.