Renovascular disease in children.
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Antihypertensive Agents↗
Biomedical subjects
J R Ingelfinger
Publications and source records attributed to J R Ingelfinger.
Regulation of intrarenal and circulating renin-angiotensin systems in severe heart failure in the rat.
OBJECTIVE: Activation of the intrarenal renin-angiotensin system may contribute to the pathophysiology of heart failure by accelerating the generation of angiotensin II at local sites within the kidneys. Activation of the local intrarenal renin-angiotensin system occurs in rats and with mild heart failure. The aim of the present study was to examine components of the circulating as well as the intrarenal renin-angiotensin system in rats with severe heart failure. METHODS: Six weeks after experimental myocardial infarction (heart failure, HF; n = 8) or sham operation (control, C; n = 6), haemodynamics and the circulating and intrarenal components of the renin-angiotensin system were studied. RESULTS: HF rats were characterised by large infarctions (scar tissue > 40% of the left ventricular circumference). In comparison to sham operated controls, large myocardial infarctions resulted in severe heart failure with decreased systolic [108(SEM 3) mm Hg v 132(3) in C; p < 0.001] and diastolic arterial blood pressure [83(3) mm Hg v 95(2) in C; p < 0.05], decreased left ventricular systolic pressure [109(3) mm Hg v 132(3) in C; p < 0.005] and increased left ventricular end diastolic pressure [27(2) mm Hg v 5(1) in C; p < 0.0001]. In rats with severe heart failure, the circulating renin-angiotensin system was activated, with an increase in plasma renin activity (3.5-fold, p < 0.05) and plasma angiotensin II concentration (threefold, p < 0.01). In parallel, the intrarenal renin-angiotensin system was activated in severe heart failure. Increases occurred in renal renin mRNA level (1.7-fold, p < 0.01), renal angiotensinogen mRNA level (1.8-fold, p < 0.05), and renal angiotensin II concentration (twofold, p < 0.05) compared to C. Intrarenal angiotensin II concentrations exceeded plasma levels by a factor of 50 and were positively correlated with renal angiotensinogen mRNA levels (r = 0.874, p < 0.001), suggesting that local synthesis is the major source of angiotensin II found in the kidney. CONCLUSIONS: The intrarenal renin-angiotensin system may be selectively activated in mild heart failure, while both circulating and intrarenal renin-angiotensin systems are induced as the extent of left ventricular function worsens.
Angiotensin II↗
Renal renin-angiotensin system in diabetes: functional, immunohistochemical, and molecular biological correlations.
Recent evidence indicates a role for the renin-angiotensin system (RAS) in the pathogenesis of glomerular injury in diabetes. To further explore the RAS in diabetes, studies were conducted in nondiabetic control rats and in moderately hyperglycemic diabetic (DM) rats. In DM rats, both acute and chronic therapy with the specific angiotensin II (ANG II) receptor antagonist losartan did not affect glomerular hyperfiltration or hyperperfusion but selectively normalized the glomerular capillary hydraulic pressure and ultrafiltration coefficient. To determine the basis of intrarenal hemodynamic responsiveness to RAS inhibition, we conducted biochemical, molecular biological, and immunohistochemical studies to assess endogenous RAS activity. Values for plasma renin concentration and serum angiotensin-converting enzyme (ACE) activity in DM rats were normal. In contrast, intrarenal renin protein content, and renin and angiotensinogen mRNAs, were increased in DM rats, suggesting disproportionate activation of the intrarenal RAS. Total renal ACE activity was significantly reduced in DM rats, but immunohistochemical studies indicated redistribution of ACE in the diabetic kidney. Proximal tubule ACE activity was reduced, but ACE immunostaining intensity was enhanced in glomeruli and renal vasculature. Together, these observations indicate increased RAS activity in those sites (glomeruli and vasculature) most likely to regulate hemodynamic function, potentially explaining the prominent responses to pharmacological blockade of ANG II formation and/or action.
Angiotensin Receptor Antagonists↗
Vascular injury induces angiotensinogen gene expression in the media and neointima.
BACKGROUND: Angiotensin II promotes growth of vascular smooth muscle cells in vitro via the autocrine production of growth factors such as platelet-derived growth factor, basic fibroblast growth factor, and transforming growth factor-beta. Furthermore, experimental studies have demonstrated that angiotensin infusion can enhance smooth muscle proliferation after balloon injury in vivo. Consistent with this, angiotensin converting enzyme inhibitors have been shown to prevent myointimal proliferation. The origin of vascular angiotensin that participate in this process is of interest. We have demonstrated the presence of angiotensinogen messenger RNA (mRNA) in the adventitial and medial layers of the rat aorta and have speculated that local angiotensinogen production may play an important role during myointimal proliferation. To provide further evidence toward this hypothesis, we compared the localization and expression of angiotensinogen mRNA in control and balloon injured vessels using in situ hybridization. METHODS AND RESULTS: Abdominal aorta of Sprague-Dawley rats were studied before or after injury with a balloon catheter. Neointimal hyperplasia developed as documented morphologically by a progressive increase in the ratio of neointimal to medial thickness from 0.17 at 1 week to 1.17 at 6 weeks after injury. Angiotensinogen mRNA was detected clearly in the adventitia and media of control and injured aorta. However, at 1 week after injury, the medial-to-adventitial angiotensinogen mRNA ratio was higher in the injured aorta, suggesting increased gene expression in the media compared with control. Of potential importance, angiotensinogen mRNA was also detected in the neointima of the injured aorta, and this was also highest at 1 week after injury. CONCLUSIONS: These data are consistent with the hypothesis that balloon injury leads to activation of the vascular renin-angiotensin system, which may participate in the myointimal proliferation.
Angiotensinogen↗
Feedback regulation of angiotensin converting enzyme activity and mRNA levels by angiotensin II.
Although renin and angiotensinogen are known to be subject to feedback regulation, the effects of angiotensin II (Ang II) on the regulation of angiotensin converting enzyme (ACE) gene expression and enzymatic activity have not yet been studied. Therefore, the effects of exogenous Ang II infusion and ACE inhibition on ACE mRNA expression were examined. Ang II was infused intravenously in male Sprague-Dawley rats for 3 days at 100 (low dose), 300 (medium dose), or 1,000 (high dose) ng/kg per minute (n = 8 for each group). Compared with control (vehicle infusion, n = 8), Ang II infusion increased plasma Ang II concentration (62, 101, 126 [p < 0.05], and 187 [p < 0.05] fmol/ml) and mean arterial blood pressure (106, 119 [p < 0.05], 134 [p < 0.05], and 125 mm Hg for control, low, medium, and high doses, respectively). Ang II infusion decreased ACE mRNA levels in the lung (57%, 52%, and 51%; p < 0.05 for each) and testis (49%, 63%, and 53% of control for low, medium, and high doses, respectively; p < 0.05 for each), two major sites of ACE synthesis. There was, albeit less pronounced, a parallel decrease in pulmonary ACE activity (4.38, 3.92, 3.07 [p < 0.05], and 3.48 [p < 0.05] nM/mg per minute for control, medium, and high doses, respectively). In contrast, serum (54, 50, 48, and 38 [p < 0.05] nM/ml per minute) and testicular (2.63, 2.08 [p < 0.05], 2.24, and 2.18 nM/mg per minute for control, low, medium, and high doses, respectively) ACE activities displayed only minimal change in animals infused with Ang II.(ABSTRACT TRUNCATED AT 250 WORDS)
Angiotensin II↗
Hypertension in childhood and adolescence.
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Acute Disease↗
Reciprocal feedback regulation of kidney angiotensinogen and renin mRNA expressions by angiotensin II.
The present study asks whether angiotensin II (ANG II), a potent inhibitor of renal renin synthesis and release, regulates renal angiotensinogen synthesis. ANG II (or vehicle) was intravenously infused into male Sprague-Dawley rats for 3 days (vehicle or 100, 300, and 1,000 ng.kg-1 x min-1, n = 8/group), significantly increasing mean plasma ANG II concentrations and raising mean arterial blood pressure (MAP). ANG II dose dependently suppressed plasma renin concentration, kidney renin concentration, and renal renin mRNA levels. In contrast, ANG II infusion increased renal angiotensinogen mRNA levels stepwise to 122, 136 (P < 0.05), and 150% (P < 0.05) of control and also increased both liver mRNA levels (P < 0.05) and plasma angiotensinogen concentration (P < 0.05). Three days of angiotensin-converting enzyme inhibition (10 mg.kg-1 x day-1 quinapril in drinking water, n = 8) significantly decreased MAP (P < 0.05) and increased both mean plasma renin concentration (P < 0.05) and renal renin mRNA levels (P < 0.005). Plasma ANG II concentration tended to decrease (not significant), and neither renal nor hepatic angiotensinogen mRNA levels displayed significant difference. However, when data from ANG II-infused and quinapril-treated rats were analyzed together, correlation between plasma ANG II concentrations and renal angiotensinogen mRNA levels was highly significant (P < 0.005, r = 0.585). Thus plasma ANG II upregulates renal angiotensinogen gene expression and downregulates renal renin gene expression, a reciprocal feedback regulation that may have important physiological consequences.
Angiotensin II↗
Differential effects of captopril and enalapril on tissue renin-angiotensin systems in experimental heart failure.
BACKGROUND: Angiotensin converting enzyme (ACE) inhibitor therapy elicits beneficial responses from patients with heart failure. We hypothesized that a major site of action of these drugs is tissue ACE and that ACE inhibitors might differ in their ability to inhibit tissue ACE. To test this hypothesis, we assessed the effects of captopril and enalapril on blood pressure and renal function and on serum and tissue ACE activities in sham-operated rats and rats with heart failure induced by coronary artery ligation. METHODS AND RESULTS: During short-term (1-week) treatment, captopril (200 mg.kg-1.day-1) and enalapril (25 mg.kg-1.day-1) elicited equipotent effects on blood pressure and inhibition of serum ACE activity (85%). The effects of long-term treatment (47 days) were then studied beginning 45 +/- 5 days after coronary ligation in four treatment groups: sham-operated, vehicle (n = 14); heart failure, vehicle (n = 10); heart failure, captopril (n = 8); and heart failure, enalapril rats (n = 7). During long-term treatment, captopril and enalapril caused comparable falls of 12-18 mm Hg in blood pressure (p < 0.01 compared with vehicle treatment). There was no change in urine volume or sodium or potassium excretion in vehicle- or captopril-treated heart failure rats; in contrast, enalapril-treated heart failure rats demonstrated 83% and 10% increases in urine volume and daily sodium excretion, respectively, compared with vehicle-treated rats (both p < or = 0.01). No significant changes in blood urea nitrogen or creatinine were observed with either treatment. Enalapril but not captopril elicited a significant decrease in serum and lung ACE activities. Captopril but not enalapril inhibited aortic ACE activity. Both agents caused a comparable inhibition of renal ACE activity. The magnitude of inhibition of renal ACE activity but not serum and vascular (aortic) ACE activities correlated with the long-term blood pressure response. Enalapril but not captopril normalized renal angiotensinogen expression; the magnitude of this effect correlated with the increase in daily urinary sodium excretion (r = -0.43; p < or = 0.005). CONCLUSIONS: These data suggest that chronic treatment with these two agents elicits differential effects on tissue ACE activities and renal angiotensinogen regulation. The differential renal effects of these agents may be important in the treatment of heart failure.
Angiotensinogen↗
Evidence for tissue-specific activation of renal angiotensinogen mRNA expression in chronic stable experimental heart failure.
The intrarenal renin-angiotensin system (RAS) may contribute to the pathophysiology of heart failure by the generation of angiotensin II at local sites within the kidneys. Angiotensin II may directly influence renal hemodynamics, glomerular contractility, and tubular sodium reabsorption, thereby promoting sodium and fluid retention in this syndrome. In the present study, we examined components of the circulating RAS as well as the intrarenal expressions of renin and angiotensinogen mRNA in rats with stable compensated heart failure (HF) 12 wk after experimental myocardial infarction. Renal angiotensinogen mRNA level in vehicle-treated HF rats increased 47%, as compared with sham control rats (P = 0.001). The increase in angiotensinogen mRNA levels was more pronounced in animals with medium (46%, P < 0.05) and large (66%, P < 0.05) infarcts than in those with small infarcts (31%, P = NS). There were no differences in liver angiotensinogen mRNA, circulating angiotensinogen, angiotensin II, plasma renin concentration (PRC), kidney renin content (KRC), and renal renin mRNA level between sham and HFv. In addition, in a separate group of rats with heart failure, we demonstrated that renal angiotensin II concentration increased twofold (P < 0.05) as compared with that of age-matched sham operated controls. A parallel group of heart failure rats (HFe, n = 11) was treated with enalapril (25 mg/kg per d) in drinking water for 6 wk before these measurements. Blood pressure decreased significantly during treatment (91 vs. 103 mm Hg, P < 0.05). Enalapril treatment in HF rats increased renin mRNA level (2.5-fold, P < 0.005), KRC (5.6-fold, P = 0.005), and PRC (15.5-fold, P < 0.005). The increase in renal angiotensinogen mRNA level observed in HFv rats was markedly attenuated in enalapril treated HF rats (P < 0.001), suggesting a positive feedback of angiotensin II on renal angiotensinogen synthesis. These findings demonstrate an activation of intrarenal RAS, but no changes in the circulating counterpart in this model of experimental heart failure, and they support the concept that the intrinsic renal RAS may contribute to the pathophysiology in this syndrome.
Angiotensinogen↗
Molecular biology techniques and their applicability to the study of diabetes and hypertension: the renin-angiotensin system as an example.
Recently developed molecular biology techniques lend themselves to the study of both normal physiology and pathophysiology. This review discusses a number of such techniques and their applicability to the study of diabetes and hypertension with the renin-angiotensin system as an example. The demonstration of specific mRNA in tissue provides strong evidence that the protein for which it encodes is expressed there. The contribution of several methods to demonstrate mRNA expression including Northern analysis, slot blot analysis, solution hybridization, in situ hybridization, run-on assays, and polymerase chain reaction are discussed in the light of how these are used to study renin-angiotensin system mechanisms. Additionally, recent developments in the study of gene transfer and identification of genes are reviewed.
Animals↗
Spectrum of renal anomalies in patients with Williams syndrome.
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Adolescent↗
Molecular biology of renal injury: emphasis on the role of the renin-angiotensin system.
The developments in molecular biology of the past decade have created a powerful technology with important, if not revolutionary, clinical applications. This review discusses the molecular biology of renal injury focusing on the renin-angiotensin system as a model, first considering the molecular physiology of the renin angiotensin system within the kidney and then considering its abnormalities in renal injury. All of the components of the renin-angiotensin system are present within the kidney and are involved in modulation of glomerular microcirculation, in proximal tubular reabsorptive function, in control of glomerular/tubular balance, in modulation of medullary blood flow, and in growth and repair of the renal tubule. A new understanding of these multiple roles of the renin-angiotensin system within the kidney is made feasible by combining physiological studies with techniques such as mRNA analysis (e.g., Northern and slot blots, in situ hybridization, and RNA protection assays), transgenic animal studies, transfection studies, and restriction fragment length polymorphism analysis. The ways in which such approaches have been used to examine the role of the renin-angiotensin system in acute renal failure, proteinuric states, renal hypertension, and diabetes mellitus are discussed.
Animals↗
Intrarenal angiotensinogen: localization and regulation.
Multiple lines of evidence (physiologic, immunohistochemical, and molecular biologic) support the presence of a complete intrarenal renin-angiotensin system (RAS). Localization of angiotensinogen messenger ribonucleic acid (mRNA) within the proximal tubule, together with demonstration of renin and converting enzyme mRNAs within the kidney, provide the most persuasive evidence for local, independent synthesis. Data from a combination of in situ hybridization studies, Northern analysis, and physiologic manipulations lead us to propose that a major site for action of a local RAS is the proximal tubule. There, locally generated angiotensins may regulate sodium reabsorption and urine pH. A variety of factors appear to regulate renal angiotensinogen. For instance sodium depletion increases the expression of renal angiotensinogen (as well as renin mRNA), as does high potassium intake and androgen administration. In pathologic states, such as experimental heart failure, and certain models of hypertension, such as the spontaneously hypertensive rat, expression of renal angiotensinogen mRNA levels is altered. It is proposed that changes in the intrarenal RAS may play a role in the maintenance of homeostasis and in the pathophysiology of various disease states.
Angiotensinogen↗
Growth Failure in Children with Renal Diseases Study: an overview from the National Institutes of Health and the Advisory Committee.
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Calcitriol↗
In situ hybridization evidence for angiotensinogen messenger RNA in the rat proximal tubule. An hypothesis for the intrarenal renin angiotensin system.
We examined angiotensinogen gene expression in rat kidney by in situ hybridization histochemistry. Using a rat cRNA probe to angiotensinogen, we demonstrated angiotensinogen mRNA to be localized predominantly in the proximal renal tubule, with considerably lesser amounts in distal tubular segments and glomerular tufts. Previous studies have localized renin immunoreactivity to the juxtaglomerular cells, glomerular tufts, and proximal tubules. Such findings provide further evidence for a local tissue renin angiotensin system within the kidney which may influence regional function. Based on our data, we hypothesize that a major site of angiotensin production is the proximal tubule. We postulate that angiotensin synthesized in and/or around the proximal tubule may directly modulate tubular transport of sodium, bicarbonate, and water. In addition to the proximal tubule, the specific localization of the renin angiotensin components elsewhere in the kidney would also support the other proposed regional functions of the intrarenal system, including modulation of tubuloglomerular balance.
Angiotensin II↗
Molecular biology and pathophysiology of the intrarenal renin-angiotensin system.
There has been considerable interest in the existence of an intrarenal renin-angiotensin system and its physiological implications. Recent demonstrations of renin, angiotensinogen and angiotensin converting enzyme messenger (m)RNAs in the kidney have provided strong evidence for the presence of an independent local system. This has been further supported by the demonstration of tissue-specific regulation of renin and angiotensinogen mRNA expression which may lead to differential systemic and intrarenal angiotensin activities. Using in situ hybridization, we have localized the intrarenal sites of gene expression and possible angiotensin production. One major site appears to be the proximal tubule, where local angiotensin can regulate sodium reabsorption and urine pH. Renin and angiotensinogen mRNA expressions are regulated by several common factors. In particular, sodium depletion stimulates the expression of both genes in the kidney, increasing the production of intrarenal angiotensin that is important in maintaining sodium homeostasis. Renal renin and angiotensinogen mRNA levels are altered in experimental heart failure and the spontaneously hypertensive rat (SHR). These changes in intrarenal renin and angiotensinogen mRNA expression may be important in the renal pathophysiology of these diseases.
Angiotensin II↗
Altered sodium regulation of renal angiotensinogen mRNA in the spontaneously hypertensive rat.
The expression of the intrarenal renin angiotensin mRNAs in Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) were investigated in rats fed a low (0.02%)- or normal (1.6%)-sodium diet for 5 days. Total RNA was isolated from the kidneys and analyzed by both Northern and slot blots. The results indicated that the kidneys of all four groups of rats containing readibly detectable levels of renin and angiotensinogen mRNAs. The kidneys of the WKY contained higher levels of angiotensinogen mRNA under normal-salt diet compared with the SHR (P less than 0.01). Mild sodium depletion stimulated angiotensinogen mRNA in WKY kidneys by almost 50% compared with normal salt diet (P less than 0.01). In contrast, there was no significant difference in the renal angiotensinogen mRNA levels in the kidneys of SHR fed a low- or normal-sodium diet. Renin mRNA concentrations were comparable in both strains. Mild sodium depletion failed to yield any detectable changes in renin mRNA levels in either strain. Thus the SHR exhibits an alteration in the sodium regulation of intrarenal angiotensinogen mRNA expression. These results may have implications in the renal physiology of these animals.
Angiotensinogen↗
Role of molecular biology in hypertension research. State of the Art lecture.
In this article we will examine the potential impact of molecular biology on hypertension research. We will review the available molecular techniques, which include gene cloning, transient and stable expressions, as well as the use of transgenic animals. To facilitate our discussion, we will focus primarily on research of the renin gene. Renin provides a useful model that illustrates the power of biotechnology in providing detailed structural and biochemical information on a complex protein that exists in low quantities in vivo. Studies of its messenger RNA and gene expression have resulted in an improved understanding of the biology of the renin system and in generating new hypotheses. These approaches can be generalized to studies of other vasoactive hormones, contractile protein, and other gene products related to cardiovascular regulation. To elucidate the role of a specific gene in genetic hypertension, we will discuss the use of genetic markers in cosegregation or linkage analysis. Finally, we will examine the potential of transgenic animals in the study of regulation of gene expression in the whole animal and the contribution of selective genes to hypertension. We believe that molecular biology complements the biochemical and physiological approaches and provides new opportunities for furthering our concept of hypertension mechanisms.
Animals↗