Increase In Angiotensinogen Research Articles

Regulation of hepatic angiotensinogen synthesis and secretion by steroid hormones.

The regulation of angiotensinogen gene expression by steroid hormones in the rat liver has been examined. In the intact animal, dexamethasone (7 mg/kg ip) and estradiol (7 mg/kg sc) caused an increase in plasma angiotensinogen, which became first apparent after 5 or 9 h, respectively, and resulted in plasma concentrations 4.6- and 1.9-fold higher than in controls at 24 h. These changes were preceded by comparable increases in hepatic angiotensinogen messenger RNA (mRNA). In contrast, dihydrotestosterone (10 mg/kg sc) failed to alter plasma angiotensinogen, although hepatic angiotensinogen mRNA and total RNA were slightly elevated. In isolated hepatocytes exposed to either dexamethasone or estradiol (10 microM each) angiotensinogen mRNA started to increase within less than 1 or 3 h, respectively, followed, with a further time lag of about 2 h, by an increase in secretion rate of angiotensinogen. Dihydrotestosterone (10 and 100 microM) induced a rapid increase in total hepatocyte RNA (1.3-fold) and angiotensinogen mRNA (2-fold) with a peak at 2 h. Surprisingly, angiotensinogen secretion remained either unaltered (10 microM dihydrotestosterone) or even decreased (100 microM dihydrotestosterone). In a hepatoma cell line (FT02B) and a subclone (Fe 33) stably transfected with the human estrogen receptor, dexamethasone and estradiol induced an increase in angiotensinogen mRNA and secretion with the same characteristics as in hepatocytes. In conclusion, in this study a direct effect of estradiol on angiotensinogen mRNA and secretion in hepatocytes could be established, which differs from that of dexamethasone by a delayed onset of action. The observation, both in vivo and in vitro, that dihydrotestosterone induced an increase in total RNA and angiotensinogen mRNA, which is not accompanied by an increased angiotensinogen secretion, cannot be explained at present. This study also demonstrates the usefulness of a hepatoma cell line stably transfected with the estrogen receptor gene for the investigation of estrogen-dependent effects in vitro.

Effect of Angiotensinogen Concentration on Renin Activity Following Nephrectomy and Adrenalectomy: Implications in the Activation of Plasma Prorenin

We have studied the effects of bilateral nephrectomy and adrenalectomy on angiotensinogen concentration, plasma renin activity, and total plasma renin activity obtained after trypsin activation in rats and compared with controls. Our results show that the plasma angiotensinogen concentration of nephrectomized (NX) rats is 5-fold higher than that of adrenalectomized (AX) rats. On the other hand, plasma angiotensinogen concentration of AX rats was about 2.5-fold lower than that of control rats. While NX rat plasma possess no renin activity, its mixing (1:1, v/v) with AX plasma results in 2-fold increase in renin activity over that observed for AX plasma alone. These results suggest that the apparent increase in renin activity upon mixing these two plasmas is at least partly due to an overall increase in angiotensinogen concentration in the mixture. To show that it is not due to activation of NX plasma prorenin by a convertase from AX plasma, prorenin-free NX rat plasma was prepared by using an anti-renin immunoaffinity column. When this prorenin-free NX plasma was mixed (1:1, v/v) with AX, again a 2-fold increase in renin activity was observed which is attributed to the overall increase in plasma angiotensinogen in the mixture. It is concluded that rat plasma prorenin is probably not activated within the circulation by a prorenin convertase from the rat kidney.

Comparison of metabolic and clinical effects of four oral contraceptive formulations and a contraceptive vaginal ring

A group of 100 women desiring OC received one of the following four formulations on a randomized basis: (1) mestranol 50 μg and norethindrone 1 mg, (2) ethinyl estradiol 50 μg and norethindrone 1 mg, (3) ethinyl estradiol 35 μg and norethindrone 1 mg, and (4) ethinyl estradiol 30 μg and levonorgestrel 150 mg. An additional 10 women received a CVR containing levonorgestrel and estradiol. Measurement of a large number of serum chemistries, lipids, proteins, clotting factors, and liver enzymes was obtained before and 3 and 6 months after starting medication. Clinical factors such as weight, blood pressure, bleeding or spotting, or any adverse side effects were also recorded. There was no significant difference in the metabolic parameters measured among the four oral contraceptives except the increase in angiotensinogen was slightly less in the groups receiving the compounds with 30 or 35 μg estrogen and the groups receiving the norgestrel compound had no increase in triglycerides and a slight decrease in cholesterol levels. When the CVR was compared with all oral contraceptives it was found to produce no change in angiotensinogen levels and a decrease in triglycerides. Some of each group of OC users had a lowering of antithrombin III to abnormal levels but none of the CVR users had this amount of decrease. As oral steroids with 30 or 35 μg of estrogen do not produce significantly less metabolic alteration than do compounds with 50 μg of estrogen, it is unlikely that their use will reduce the incidence of the uncommon serious adverse effects associated with OC use. However, since the CVR's did not increase angiotensinogen, their use as contraceptives will most likely not produce hypertension and possibly the other serious circulatory problems which are increased in some OC users.

THE RENIN SYSTEM IN MICE

In different strains of mice the sum of renal and submaxillary renin was found to vary from about 10 to about 1000 Haas‐Goldblatt units, about 7 to well over 98 per cent of which was found in the submaxillary glands. The plasma renin and angiotensinogen concentrations were independent of these variations. Following submaxillary sialo‐adenectomy there was only a slight decrease, if any, in plasma renin or increase in plasma angiotensinogen. Contrary to this, nephrectomy was followed by a marked decrease in plasma renin and a marked increase in plasma angiotensinogen, both of which were independent of the highly varying amount of submaxillary renin left in the organism. The postnephrec‐tomy increase in angiotensinogen was further independent of variations in the pre‐operative plasma and renal renin, supporting the previous conclusion that it must be due to loss of some internal factor other than renin or to loss of some external renal function.

Effects of sex hormones on the renal pressor system.

The effects of sex and sex hormones on angiotensinogen, renin activity, and renin concentration in plasma and on renal renin were investigated in rats. During estrus there was a significant increase in angiotensinogen, which was suppressed by ovariectomy. In males, castration had no effect. Administration of stilbestrol caused a rapid increase in angiotensinogen. Renal renin and plasma renin concentration decreased while plasma renin activity remained near normal levels. Following addition of a constant dose of rat renin, plasma from estrogen-treated rats released angiotensin at a faster rate than normal plasma; this increased reactivity is attributed to the high substrate concentration and not to the lack of an inhibitor, to the presence of an activator, or of a more reactive substrate. These changes were not modified by progesterone or testosterone. Progesterone alone caused a significant increase in renal renin. Estrogens did not elicit hypertension nor modify a preexisting renal hypertension. These observations support the hypothesis that the primary effect of estrogens is an increased angiotensinogen formation, and that the resulting enhancement in plasma reactivity to renin causes an increase in angiotensin which acts as a negative feedback on renin production.

CAUSE OF INCREASED PLASMA ANGIOTENSINOGEN AFTER NEPHRECTOMY

24 hours after nephrectomy there is an increase in plasma angiotensinogen which is 2 to 3 times increased in unilaterally nephrectomized rats and 5 to 12 times increased in bilaterally nephrectomized rats. In normal rats, DOCA + salt treated rats and renal hypertensive rats, the postnephrectomy changes are about the same, independent of the marked differences in their pre‐operative plasma and renal renin. The postnephrectomy increase in angiotensinogen must therefore be due to loss of some internal factor other than renin or to loss of some external renal function. Both shamoperation and unilateral nephrectomy are followed by a marked decrease in plasma renin, the postoperative fall being more pronounced after removal of a clamped kidney than after removal of a normal.

Influence of diethylstilbestrol on the renin-angiotensin system of male rats.

Diethylstilbestrol (0.25 mg/100 g body weight) was given to normal, waterdeprived and adrenalectomized rats. Angiotensinogen was measured by a substrate exhaustion technique and plasma renin by the micro-method of Boucher et al., slightly modified. The in vitro measurement of plasma renin was always performed with an excess of homologous substrate. An increase in the renin substrate was the primary effect of estrogens on the renin-angiotensin system. This increase in angiotensinogen was consistently accompanied by a decrease in plasma renin, and the same inverse relationship between substrate and renin was observed in normal rats. In adrenalectomized rats increase of plasma renin was not modified by changes in substrate. In this condition, estrogens were unable to make the sodium balance positive and to increase plasma volume. The following sequence of events may be proposed: Estrogens increase substrate, which is not present in excess. The consecutive increased formation of angiotensin stimulates the min...

Augmentation of pressor response to renin and increased renin release in rats with mercuric chloride intoxication and with bilateral ureteral ligation.

The present investigation was planned (1) to determine the pressor response to renin and (2) to examine the changes in plasma and renal renin levels in rats with mercuric chloride intoxication and with bilateral ureteral ligation. A marked augmentation of pressor response to renin was observed in these rats as well as in nephrectomized. Since in the preliminary experiments the authors had confirmed an increased plasma concentration of renin substrate (angiotensinogen) in all of these animals, it was considered that the augmented response to renin may be mainly attributable to the increase of angiotensinogen in the blood. In mercuric chloride intoxication and also in bilateral ureteral ligation an increased renin release was demonstrated, while in nephrectomy renin disappeared from the organism. Accordingly, the postulation that the increase in angiotensinogen is a result presumably of the removal of a source of renin by nephrectomy would not be applied to the cases of mercuric chloride intoxication and bilateral ureteral ligation. Some possible mechanisms responsible for these phenomena were discussed.