Synthesis of angiotensinogen by isolated rat liver cells and its regulation in comparison to serum albumin.
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Angiotensin II↗
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The distribution of angiotensinogen in dog brain studied by cell fractionation.
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Acid Phosphatase↗
Evidence for an angiotensinogenic mechanism of the hypertension of Cushing's syndrome.
The blood pressure response to the angiotensin II analog 1-sar-8-ala-angiotensin II, or saralasin, was studied in five patients with clinical and laboratory evidence of Cushing's syndrome. Plasma renin activity, plasma renin substrate, and plasma renin concentration were measured in all five patients. The renin system and the response to saralasin were measured after furosemide administration. Plasma aldosterone was measured after infusion of 2 liters normal saline. All patients studied showed a hypotensive response to saralasin, the mean BP changing from 163/108 mm Hg to 130/85 mm Hg (P less than 0.02). There was a significant elevation of the plasma renin activity and plasma renin concentration in the patients compared to normal subjects, although plasma renin substrate was not significantly different from normal values. There was normal suppression of plasma aldosterone after the infusion of 0.9% saline. The findings indicate that the hypertension of these patients with Cushing's syndrome was mediated in large part by angiotensin II.
Adrenal Glands↗
Exchangeable sodium in angiotensinogenic and nonangiotensinogenic renovascular hypertension.
Previous studies have suggested that angiotensin II and sodium can act as alternative mechanisms in maintaining high blood pressure in chronic renovascular hypertension, In the present study, exchangeable sodium was measured in rats in which angiotensin II has been confirmed or excluded as the main cause of the hypertension. To determine the degree of participation of angiotensin II in the maintenance of the high blood pressure, we studied the mean blood pressure response to an angiotensin antagonist (1-Sar-8-Ala-angiotensin II) and to a converting enzyme inhibitor (SQ20,881). Rats with a decrease in blood pressure of less than 20 mm Hg, in response to both inhibitors, were classified as nonresponders; those with a decrease of 20 mm Hg or more, as responders. Fifty percent of the rats with two-kidney hypertension were nonresponders, and they had lower blood pressure and plasma renin activity than the responders. Further, these two-kidney, hypertensive, nonresponder rats had normal exchangeable sodium. The two-kidney hypertensive responders, on the other hand, had significantly higher exchangeable sodium than both the two-kidney, hypertensive nonresponders and the two-kidney control rats. These results suggest that angiotensin II and exchangeable sodium do not play a major role in the maintenance of the high blood pressure in the two-kidney hypertensive nonresponders. However, there appears to be an abnormal relationship between renin and exchangeable sodium in the two-kidney hypertensive responders that could contribute to the maintenance of the hypertension.
Angiotensin I↗
Evidence against acetone-soluble renin inhibitors in normal human plasma.
The presence of acetone-soluble renin inhibitors in normal plasma has been proposed to explain the variation of plasma reactivity (PRR) in samples from normotensive and hypertensive subjects. In our experience, acetone extraction decreased PRR in relation to unextracted control values, an observation which is not consistent with the circulating lipid-renin inhibitor hypothesis. Exposure to acetone at -40 degrees C for 1 minute invariably denatured some endogenous angiotensinogen. The PRR in extracted and unextracted plasma was positively correlated with the concentration of available angiotensinogen, r = 0.955 (p < 0.05), and r = 0.964 (p < 0.01), respectively, but the addition of exogenous substrate did not uniformly increase PRR in acetone-treated plasma above control values. These data argue against the use of acetone extraction to demonstrate the existence of circulating lipid-renin inhibitors. Acetone removed 14% to 25% of the normal plasma lipids and although the extract contained most of the major lipid classes, neutral lipids were the most abundant (73% by weight). The presence of acetone-soluble phospholipids appeared to increase angiotensin I formation in the partially purified renin-angiotensinogen system, but phospholipids interfered with the radioimmunoassay and resulted in an overestimation of angiotensin I. Plasma neutral lipids decreased in vitro renin activity by 13% (p < 0.025) but this degree of inhibition suggests that lipid-renin interactions may have minimal in vivo physiological significance. In contrast to previous reports, we found the correlation between PRR and endogenous angiotensinogen in normotensive and hypertensive plasmas to be statistically significant (r = 0.643, p < 0.01). Inactivated human angiotensinogen was also shown to be an inhibitor of renin in vitro. This effect could have possibly influenced PRR values that were determined by others in the presence of inactivated angiotensinogen.
Acetone↗
Isorenin, pseudorenin, cathepsin D and renin. A comparative enzymatic study of angiotensin-forming enzymes.
1. Renin was purified 30 000-fold from rat kidneys by chromatography on DEAE-cellulose and SP-Sephadex, and by affinity chromatography on pepstatinyl-Sepharose. 2. The enzymatic properties of isorenin from rat brain, pseudorenin from hog spleen, cathepsin D from bovine spleen, and renin from rat kidneys were compared: Isorenin, pseudorenin and cathepsin D generate angiotensin from tetradecapeptide renin substrate with pH optima around 4.9, renin at 6.0. With sheep angiotensinogen as substrate, isorenin, pseudorenin and cathepsin D have similar pH profiles (pH optima at 3.9 and 5.5), in contrast to renin (pH optimum at 6.8). 3. The angiotensin-formation from tetradecapeptide by isorenin, pseudorenin and cathepsin D was inhibited by albumin, alpha-and beta-globulins. These 3 enzymes have acid protease activity at pH 3.2 with hemoglobin as the substrate. Renin is not inhibited by proteins and has no acid protease activity. 4. Renin generates angiotensin I from various angiotensinogens at least 100 000 times faster than isorenin, pseudorenin or cathepsin D, and 3000 000 times faster than isorenin when compared at pH 7.2 with rat angiotensinogen as substrate. 5. The 3 'non-renin' enzymes exhibit a high sensitivity to inhibition by pepstatin (Ki less than 5.10(-10) M), in contrast to renin (Ki approximately 6-10(-7) M), at pH 5.5. 6. It is concluded from the data that isorenin from rat brain and pseudorenin from hog spleen are closely related to, or identical with cathepsin D.
Albumins↗
Studies on the activity of the renin-angiotensin-aldosterone system (RAAS) in patients with cirrhosis of the liver.
Plasma renin activity (PRA), plasma renin concentration (PRC), angiotensinogen, angiotensin II (AT II) and plasma aldosterone were determined by radioimmunoassay in 77 patients with cirrhosis of the liver [group I: with ascites, untreated (n=23); group II: patients with ascites during treatment (n=32); group III: after removal of fluids, but under further spironolactone therapy (n=10); group IV: untreated subjects without ascites (n=12)]. With the exception of decreased angiotensinogen values in all groups ranging between 39% (group IV) and 73% (group III) no significant changes of the other parameters of the RAAS were found in untreated patients. A highly significant increase of PRA, PRC, AT II and plasma aldosterone was observed in treated cirrhotics with (group II) or without (group III) ascites. In the total series of patients AT II was closely related to PRA, PRC and aldosterone emphasizing aldosterone secretion. Plasma sodium was inversely correlated to PRA, PRC, AT II and aldosterone, but no relationship was detected between these parameters of the RAAS and plasma potassium. Our results indicate that hyperaldosteronism in cirrhosis appears unlikely to be the major determinant of avid renal sodium retention and ascites formation. An increased activity of the RAAS is most often initiated by therapeutic factors and/or markedly altered electrolyte metabolism. Therefore, basal conditions of the patients to be studied must be well defined to exclude any artificially induced stimulation of the RAAS.
Adult↗
In vivo enzyme activity of purified human brain renin.
Cerebrospinal fluid (CSF) of rats contains high angiotensinogen concentrations. When 3500-fold purified renin from human brain was injected into the brain ventricles of rats, angiotensin I concentrations increased from undetectable levels to 147.9 +/- 18.8 fMol per ml CSF. In parallel, mean arterial blood pressure increased from 93 +/- 2.4 mm Hg to 107 +/- 3.7 mm Hg. The increase in blood pressure could be abolished by intraventricular administration of saralasin, a blocker of angiotensin II receptors. Intraventricular injection of cathepsin D had no effect on arterial blood pressure and the agiotensin I concentration in CSF remained below detection limits of the radioimmunoassay. We conclude that brain renin acts on endogenous brain angiotensinogen under physioloical in vivo conditions to form angiotensin I. The latter is converted to angiotensin II and leads to biological effects, i.e. increase of blood pressure.
Angiotensin I↗
Purification and partial characterization of rat brain acid proteinase (isorenin).
1. Isorenin was purified 2000-fold from rat brain by a simple 3-step procedure involving affinity chromatography on pepstatinyl-Sepharose, The preparation appears as a homogenous protein in analytical polyacrylamide gel electrophoresis. Sodium dodecyl sulfate gel electrophoresis indicated an apparent molecular weight of 45 000. Isoelectric focusing separated isoenzymes with isoelectric points at pH 5.45, 5.87, 6.16 and 7.05. 2. The enzyme generates antiotensin I from tetradecapeptide (pH optimum 4.7) and from sheep angiotensinogen (pH optima 3.9 and 5.5). The rate of angiotensin I formation from tetradecapeptide was 30 000 times higher than that from sheep angiotensinogen. The enzyme has acid protease activity at pH 3.2 with hemoglobin as the substrate and pepstatin is a potent inhibitor of the enzyme with a Ki of less than 10(-9) M. 3. The properties of the enzyme strongly suggest that it is identical with cathepsin D.
Angiotensin I↗
Pure Renin. Isolation from hog kidney and characterization.
The pressor enzyme renin (EC 3.4.99.19) was isolated in a pure and stable form from hog kidney by affinity chromatography on a pepstatin/agarose gel followed by three additional steps of conventional chromatography. Destruction of the enzyme by proteolysis during isolation was prevented by chemically eliminating proteases in extracts. The pure preparation was used for the characterization of this enzyme. Renin was found to be a glycoprotein containing glucosamine and possessing binding affinity to concanavalin A. Contrary to previous reports, pure renin is stable at neutral pH either at 4 or -20 degrees for 3 to 8 weeks. It has a molecular weight of 36,400 as determined by equilibrium ultracentrifugation, an isoelectric point of 5.2 and E1%1cm (280 nm) of 9.1. In contrast to crude preparations, the enzyme activity has a broad pH optimum between pH 5.5 and 7.0 for both hog angiotensinogen and the synthetic octapeptide substrate benzyloxycarbonyl-Pro-Phe-His-Leu-Leu-Val-Tyr-Ser-beta-naphthylamide. The rate of formation of angiotensin I from hog angiotensinogen at pH 6.0 and 37 degrees was 267 microng/h/microng of renin, or 2000 Goldblatt units/mg of renin. For the synthetic fluorogenic octapeptide substrate benzyloxycarbonyl-Pro-Phe-His-Leu-Leu-Val-Tyr-Ser-beta-naphthylamide, a Km of 33 micronM and a Vmax of 0.94 micronmol/h/mg of enzyme were obtained at pH 6.5 and 37 degrees.
Angiotensinogen↗
Improvement of renin determination in human plasma using a commonly available renin standard in a radioimmunological method.
UNLABELLED: A new method for the measurement of renin in human plasma is described. The method is based on the introduction of the internationally available renin standard of the Medical Research Council (MRC) London, as a calibration system. Thus, some principal disadvantages of methods expressing results in renin reaction velocity (angiotensin generation rate) only are avoided. Both renins, unknown and standard, react with a sheep substrate preparation and are handled identically throughout the whole procedure including the angiotensin I radioimmunoassay (RIA). The plasma renin concentration (PRC) is given in 10(-6) MRC-renin units (muM/ml). RESULTS: the renin standard is free of angiotensin, angiotensinases, and angiotensinogen; it is stable on storage. Identical enzyme kinetics are shown for both renins. An interference between endogenous and exogenous substrate could be avoided. The potentially harmful influences of proteins from the enzyme incubation mixture of the RIA dose response curve are shown. The use of an angiotensin I calibration system could be omitted. Using a standard renin dilution from 250-0.9 muU/ml also the full biological range is covered. When giving an unrestricted diet the preliminary normal values of PRC are 21.9 +/- 12.6 muU/ml in recumbent and 40.1 +/- 19.8 muU/ml in upright position (n = 16,x +/- s, age 20-35 years). Earlier findings of age-dependency of PRC were confirmed.
Adult↗
The influence of vinblastine and colchicine on renin secretion in vivo and in vitro.
The effect of the microtubule inhibitors colchicine and vinblastine on renin release in vivo and in vitro was studied. Injection of 0.5 mg/100 g i.v. of colchicine or vinblastine to furosemide treated rats on a low salt diet resulted in a decrease of plasma renin as well as plasma angiotensinogen concentration during a 5 h observation period. Renin release from rat kidney slices was diminished by vinblastine (5 x 10(-5) M), when basal or stimulated (by isobutylmethylxanthine and isoproterenol) renin release was measured. Colchicine at 5 x 10(-5) M had no effect under these conditions. Renin release from the isolated perfused rat kidney was increased 2--3 fold by vinblastine (10(-5) M) or colchicine (10(-4) M). The maximal response of renin release to isoproterenol (10(-7) M) was not changed when vinblastine (10(-5) M) or colchicine (10(-4) M) were present in the perfusion medium. The contrasting results cast considerable doubts on the suitability of microtubule inhibitors in studies on renin secretion.
Angiotensinogen↗
Methodologic problems in plasma renin activity measurements.
The influence of pH and angiotensinase inhibitors on the in vitro generation of angiotensin I during PRA measurements has been investigated. PRA values obtained at pH 5.7 are higher than those obtained at pH 7.4. At pH 5.7, values obtained using diisopropylfluorophosphate (DRP 9 mM) as an angiotensinase inhibitor are higher than values obtained with a mixture of dimercaprol (BAL, 1.6 mM) and hydroxyquinoline (8-OHQ, 3 to 4 mM). Since the two methods for inhibiting angiotensinase are completely and equally efficient, it is suggested that these inhibitors might interfere with the renin angiotensinogen reaction. Significant correlations are observed between the PRA values obtained by the different methods which have been studied. Using an incubation pH of 5.7, and BAL and 8-OH quinoline as angiotensinase inhibitors, the distribution of PRA values in a population of 124 hospitalized hypertensive patients ingesting a normal sodium diet had been studied, and it has been demonstrated that the sensitivity of this method of measurement can detect small changes in PRA in patients with low renin activity.
Adenoma↗
Iso-renin of extrarenal origin. "The tissue angiotensinogenase systems".
Enzymes, similar to kidney renin, are present in extrarenal tissue of most mammals; they hydrolyze angiotensinogen to form angiotensin I. We suggest that these enzymes be called angiotensinogenases. Angiotensinogenase concentrations in extrarenal tissue can exceed those in the kidney. The enzyme has been obtained in pure crystalline form. Angiotensinogenases are part of a complex enzyme system which leads to local production of angiotensin. Results indicating a biologic role of the angiotensinogenase system in brain, adrenal gland, uterus and tissue culture are discussed.
Adrenal Glands↗
Multiple forms of renin substrate in human plasma.
Renin substrate (angiotensinogen) in unfractionated human plasma has been shown to exist in multiple forms by DEAE-cellulose chromatography and isoelectric focusing. Two major and 5 to 6 minor peaks were resolved by using a descending pH gradient elution from DEAE-cellulose columns. The two predominant forms were eluted at or near pH 4.8 and 4.4 and usually accounted for 40--50% of the recovered substrate activity. The elution pH values of the various forms were nearly constant among plasmas from normal males and females and in diabetes, early and late pregnancy and estrogen substitution therapy. The relative distribution of components was not affected by prior freezing of the plasma or by dialysis against the column buffer. Eight renin substrate forms were clearly resolved during isoelectric focusing of plasma from a woman on estrogen substitution therapy. Four of these focused at pH 4.79, 4.88, 4.94 and 5.02 in 1% (w/v) ampholytes pH 3.5--5 and were nearly equal in substrate amount. Together these 4 forms constituted 66% of the total recovered activity. A similar pattern but with decreased amounts of each form of substrate was obtained with normal plasma.
Angiotensinogen↗
Autoregulation of plasma flow in the isolated perfused rat kidney.
1. Autoregulation of renal plasma flow, by which flow remains constant despite changes in perfusion pressure, was studied in the isolated, perfused kidney of the rat. 2. Autoregulation did not occur in preparations perfused with a protein-free medium consisting of a balanced ionic solution resembling rat plasma in which 3% polyvinylpyrrolidone replaced the plasma proteins, changes in perfusion pressure over the normal autoregulatory range 100-150 mmHg produced a corresponding and linear change in venous outflow and no consistent change in renal vascular resistance. 3. Addition of human serum (5%, v/v) to the medium restored autoregulation; changes in perfusion pressure in the range 100-150 mmHg resulted in a stable plasma flow and a linear change in renal vascular resistance. The addition of bovine serum albumin (3 g/1.) to the protein-free medium restored autoregulation to a similar degree. 4. In kidneys perfused with the protein-free medium, the sensitivity of the renal vasculature to the vasoconstrictor drugs epinephrine and angiotensin II was only 1/40 the level seen in those kidneys perfused with media containing serum or albumin. 5. The experiments show that in the isolated, perfused kidney, autoregulation of plasma flow is not dependent on the presence of the globulin, angiotensinogen, in the perfusion medium; and suggest that failure of autoregulation in kidneys perfused with a protein-free medium could be attributed to the rapid decline in the sensitivity of the vascular smooth muscle to constrictor stimuli.
Angiotensin II↗
Angiotensin signaling is essential for stress erythropoiesis but causes retention of dysfunctional mitochondria in RBCs.
We previously reported that excessive angiotensin-II→AT receptor-1 (AT→ATR1) signaling results in sickle cell anemia-associated (SCA-associated) nephropathy. Herein, we showed that hyperangiotensinemia in SCA results from high erythroid cell-generated reactive oxygen species (ROS), which oxidized angiotensinogen (ATGN) and favored its rapid conversion to AT. Increased AT→ATR1 signaling in SCA erythroid cells generated ROS and created a positive feedback loop of ROS→oxidized ATGN→AT→ATR1→ROS, perpetuating the hyperangiotensinemia. ATR1 blocker, losartan, reduced erythrocyte ROS, oxidized ATGN, and AT levels. The ROS→AT→ATR1→ROS loop was driven by sickle erythropoiesis, as it was reproduced when WT mice were transplanted with SCA hematopoiesis. Using SCA and WT mice with germline- and erythroid-specific ATR1 deficiency, we found that stress erythropoiesis, but not steady-state erythropoiesis, was critically dependent on erythroid AT→ATR1 signaling, which acted in harmony with increased erythropoietin signaling. Furthermore, instead of the canonical AT→ATR1→NADPH-oxidase→ROS signaling in steady-state erythropoiesis, AT→ATR1 signaling in stress erythroid cells increased mitochondrial mass and dysfunctional mitochondria, which thereby increased ROS. SCA mice with erythroid-specific ATR1 deficiency had decreased RBC accumulation of dysfunctional mitochondria and decreased ROS, which reduced SCA-associated nephropathy. Overall, we demonstrate that AT→ATR1 signaling was essential for stress erythropoiesis but led to increased dysfunctional mitochondria retention in mature RBCs, which generated ROS and perpetuated hyperangiotensinemia, resulting in end-organ damage.
Animals↗
[State of the neurohumoral regulatory system in circulatory insufficiency].
A moderate elevation of the daily excretion of free noradrenaline and adrenalin is observed in chronic circulatory insufficiency, beginning with Stage IIA. The catecholamines metabolism is elevated, as shown by the daily excretion of normethanpherine and methanpherine and of vanillyl-mandelic acid. The activity of renin and angiotensinases was growing along with the progressing cardiac insufficiency. The blood level of angiotensinogen was decreasing, especially in patients with Stage IIB and III of decompensation. The daily excretion of aldosterone was growing along with the development of cardiac insufficiency. The functional state of the glucocorticoid function of the adrenal cortex was of a phased nature in cases of circulatory insufficiency. The study of the functional state of the epiphysis was conducted by way of determining the blood level of melatonine and of its daily excretion. In Stages I and IIA the level of this hormone was clearly elevated, in Stages IIB and III -- decreased as compared with the initial and normal levels. The plasma level of the antidiuretic hormone was distinctly growing, beginning with Stage IIB, reaching its maximal values in Stage III.
17-Ketosteroids↗