Control of Enzymatically Inactive Renin in man under Various Pathological Conditions: Implications for the Interpretation of Renin Measurements in Peripheral and Renal Venous Plasma

Abstract

1. Human plasma contains two types of renin: one is active in its native form (active renin), the other has renin-like activity after exposure to low pH (inactive renin). Reactions of acid-activated plasma renin and kidney renin with either homo logous or heterologous substrate showed identical K m values.2. Peripheral venous values for active and inactive renin in essential hypertension (n = 22), renovascular hypertension (n = 14), primary aldosteronism (n = 12), adrenal insufficiency (« = 6) and control subjects (n = 13) were directly correlated. But the percentage of renin that was active varied widely.3. After bilateral nephrectomy in 12 patients both active and inactive plasma renin fell, but did not completely disappear. Estimates of half-life in two patients were 30-80 min for active renin and 150-165 min for inactive renin.4. Renal vein to peripheral vein ratios of active and inactive renin in ten patients with essential hypertension (19 determinations) ranged from 0-96 to 1·60 and from 0-68 to 1-44 respectively with mean values (±SEM) of 1-21 ± 0-04 and 1·06 ± 0-05.5. The renal vein to peripheral vein ratio of active renin on the affected side in 13 out of 17 patients with renovascular hypertension was above the range found in essential hypertension. Six of them also had an elevated ratio of inactive renin on that side, which indicated renal release of this form of renin into the circulation. But, in contrast to the renal vein to peripheral vein ratio of active renin, the mean value of the ratio of inactive renin on the affected side was not significantly higher than on the contralateral side. The results suggest a renal mechanism not only for controlling the total quantity of circulating renin but also for modulat ing its degree of activation.

Molecular Biology of Human Renin and Its Gene

“…Whereas most investigators have concluded that there is no conversion of prorenin to renin in the circulation [1,12,14,15], it has been reported that the rat kidney releases a protease that cleaves renin in the circulation [39]. Others have proposed that prorenin might have in vivo activity, for example, through reversible activation or after its uptake by peripheral tissues [ 12,21,40].…”

“…It was of particular interest to determine whether prorenin was converted to renin in these cells, because the only known sources of plasma renin in humans and rats are the kidneys [ l, 12,14,15]. Most other tissues that have been found to express the renin gene apparently release only prorenin [ 12,14,[20][21][22][23][24][25][26][29][30][31].…”

“…The major source of circulating renin in man is the renal juxtaglomerular cells, in which renin mRNA is translated into preprorenin that is processed to prorenin upon its insertion into the rough endoplasmic reticulum [1,2,[12][13][14][15]; prorenin is catalytically inactive [12,16]. Some prorenin is released [17,18], but much of it is converted in the juxtaglomerular cells to active renin by proteolytic removal of the 43 amino acid prosegment [10,11,[16][17][18].…”

Age and the pharmacodynamics of angiotensin converting enzyme inhibitors enalapril and enalaprilat.

“…The pharmacodynamic responses to these agents have been claimed to be directly related to plasma renin activity (Case et al, 1977), which falls with age (Meade et al, 1983 (Hockings et al, 1985). The pharmacokinetics of enalaprilat in these subjects is described in a separate paper (Hockings et al, 1986 Blood pressures and heart rate recordings were made at these times by means of a semi- Derkx et al, (1978). Angiotensin I generated during incubation of buffer and plasma at 37°C was measured by radioimmunoassay.…”

Active, inactive and total renin concentrations in plasma of hypertensive patients.

“…The measurements of plasma inactive renin reported by many authors are widely scattered (Derkx et al 1976(Derkx et al , 1978Leckie et al 1977;Sealey et al 1977 a,b ;Kappelgaard et al 1978;Millar et al 1980). Where does this inconsistency come from?…”