Multiple forms of human plasma renin substrate.

Abstract

A B S T R A C T The objective of this investigation was to determine whether heterogeneity of plasma renin substrate could be observed in states of steroid excess and various forms of hypertensive disease. In states of stimulated renin substrate production by estrogens or glucocorticoids, multiple forms of renin substrate were apparent when stimulation was excessive. Stimulation of substrate production caused by uremia associated with hypertension showed similar results. None, or only trace quantities of the additional forms of renin substrate were evident in subjects with normal or suppressed levels of plasma renin substrate. The additional forms of renin substrate could be distinguished from the normal form on the basis of crossreactivity with a specific antiserum to the normal form, electrophoretic mobility, and kinetic rate constants. Differences in rate constants of the various forms of plasma renin substrate may account for the altered rate of the renin reaction associated with several states of hypertension. In plasma of patients with renovascular hypertension, significant quantities of a protein which cross-reacted with the antiserum but could not generate angiotensin I were observed. INTRODUCTION We have previously described the purification of renin substrate from normal human plasma (1) and the development of a direct radioimmunoassay for this protein (2). The direct assay for renin substrate in normal human plasma was validated by demonstrating a 1:1 correlation to substrate measured by the generation of angiotensin I by prolonged incubation with exogenous homologous renin (indirect method). Results of preliminary experiments indicated, however, that in plasma samples in which renin substrate concentration was elevated at least 2 SD above normal as measured by angiotensin I generation, the direct as-

Formation of high-molecular-weight angiotensinogen during pregnancy is a result of competing redox reactions with the proform of eosinophil major basic protein

“…AGT antigen eluted as a major peak corresponding to monomeric AGT (fractions 37-46) and a smaller broad peak of HMW AGT (fractions [29][30][31][32][33][34][35][36][37][38]. The total amount of AGT in the HMW fractions relative to monomeric AGT is in fair agreement with previous studies [7,8].…”

“…How the network is regulated in vivo is not known, but differences in the balances between the covalent complexes have been recognized. For example, the fraction of AGT present as HMW complexes (approximately 16 % in normal pregnancy [7,8]) has been found to vary and to be associated with the development of pregnancy-induced hypertension and pre-eclampsia [7,35,36], the latter associated with hypoxia and therefore redox changes [37]. Also, the fraction of PAPP-A present as active uncomplexed PAPP-A is not constant, but varies from about one third in the first trimester to less than 1 % at term [38], causing a many-fold difference in specific PAPP-A activity.…”

Differences in the kinetic rate constants of normal and high molecular weight renin substrate from term pregnancy human plasma.

“…Heterogeneity of renin substrate in human plasma has also been reported by several investigators (Eggena et al, , 1978Printz, 1977). The effect of estrogens on the renin-angiotensin system is also of interest in view of the increasingly recognized occurrence of hypertension in women taking oral contraceptives.…”

“…We have previously reported (Eggena et al, , 1978Shionoiri et al, 1983) on the increase in renin substrate and development of several different forms of renin substrate with different molecular weight, and electrophoretic mobility, occuring in the plasma of pregnant women or women taking oral contraceptives. In this study, there are two major findings, namely that the kinetic constants for the renin-renin substrate reaction are different between the high-molecular weight substrate (HMS) and the normal molecular weight substrate (NMS), and that the rate of the renin reaction is greatly increased when a small amount of the HMS is added to the NMS compared to that found in the NMS alone.…”

Placental Regulation of Peptide Hormone and Growth Factor Activity by proMBP1

“…The HMW AGT fraction increases in the circulation of women on oral contraceptives (10%) and during pregnancy (16%), and it may become the predominant form in pathological conditions, such as hypertension and preeclampsia [100][101][102]. HMW AGT is a major component of the placental-specific RAS and is the predominant form in amniotic fluid and placental extracts, and the increased fraction of circulating HMW AGT is believed to be of placental origin [103,104].…”