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Molecular Biology of Renin and Regulation of Its Gene
Acknowledgments
The authors would like to thank Chantal Mercure for the gift of previously unpublished images presented in Figs. 21.1 and 21.2 . This work was supported by an unrestricted grant from Merck-Frosst Canada Ltd. to TLR.
1
Introduction
Renin, a member of the aspartyl protease family of enzymes, is released into the circulation from the juxtaglomerular (JG) cells of the kidney where it cleaves angiotensinogen primarily of hepatic origin to form angiotensin I (Ang I). Ang I is further processed to angiotensin II (Ang II) by angiotensin-converting enzyme (ACE) abundantly present both in the plasma and on the surface of endothelial cells. Ang II causes vasoconstriction through its effects on the vasculature and sodium retention both through its direct effects on the renal tubules and via its effects on adrenal synthesis and secretion of aldosterone. Modulation of renin–angiotensin–aldosterone system (RAAS) activity is therefore a critical determinant of blood pressure and fluid volume.
In humans, the release of renin from JG cells represents the rate-limiting step in the RAAS cascade. Because the circulating concentration of angiotensinogen (roughly 1.3 μM) is very close to the K of renin for angiotensinogen (1.15 μM), the rate of generation of angiotensin peptides is directly affected by changes in both renin and substrate levels. Renin, itself, is first synthesized as an enzymatically inactive precursor, prorenin. Conversion of prorenin to active renin occurs before secretion from JG cells which release both prorenin and renin into the circulation. The secretion of prorenin is thought to be constitutive, whereas that of renin is regulated by physiological stimuli. However, as has become increasingly apparent, physiological stimuli affecting renin secretion also impact on renin gene expression and hence prorenin secretion. Overall, the activity of the RAAS hinges on the level of renin gene expression and on the efficiency with which prorenin is converted to active renin. The goal of this chapter is to review what is known about these two biological processes.
2
Production and Activation of Renin
2.1
Tissue Origin of Active Renin
Active renin in the plasma comes almost entirely from the kidneys. Total nephrectomy of both humans and animals causes plasma renin levels to disappear. In addition to active renin secreted from JG cells, prorenin is also present in the plasma at levels 5–10 times that of active renin. After nephrectomy, circulating prorenin declines, but does not disappear, suggesting that it is secreted from sites outside of the kidneys. Indeed, expression of the renin gene has been detected in a number of extrarenal tissues including the adrenal and pituitary glands, the eye, and reproductive tissues, and it is therefore likely that these tissues contribute to prorenin found in the circulation.
While the renal JG cells release both prorenin and renin, they do so by different mechanisms: the secretion of prorenin is only limited by its rate of synthesis and this type of secretion has been called constitutive. Renin, on the other hand, is only generated once prorenin enters the lysosome-like secretory granules of the JG cell. Renin is stored in these dense secretory granules ( Fig. 21.1 ) and is subsequently released in response to various physiological stimuli. It is estimated that about one-fourth of the prorenin made in JG cells is sorted to secretory granules where it is converted to renin. Release of JG cell granules thereby provides a “rapid response” mechanism to increase active renin content in the circulation while the modulation of renin gene expression provides a more long-term modulation of renin and prorenin production.
2.2
Physiological Control of Renin Levels
Because only the JG cells of the kidneys produce active renin, it is not surprising that the mechanisms that regulate normal renin secretion and renin gene expression reside primarily in the kidneys. JG cells repress the release of renin in response to high salt in the distal tubule (through mechanisms mediated by the macula densa) as well as increases in Ang II and/or the concomitant rise in blood pressure. In contrast, renin release increases in response to sympathetic stimulation, low blood pressure, or blockade of Ang II signaling or production as well as decreases in distal tubular sodium. The physiological regulation of renin release will be dealt with in more detail in Chapter 12 .
Defects in the physiological control of renin release may also play an important part in the contribution of the RAAS to disease. Although only about 10% of all hypertensive patients have elevated plasma renin levels, even a normal plasma renin level in a hypertensive patient is inappropriate because the high blood pressure should suppress renin secretion. Therefore, hypertensive patients should have low plasma renin levels if their RAAS is responding normally, and normal as well as high plasma renins should be considered an abnormality in a hypertensive patient’s ability to suppress plasma renin in response to their elevated blood pressure. The dependence of an individual’s blood pressure on plasma renin is reflected by their responsiveness to antirenin drugs. Conversely, in hypertensives with low plasma renin levels, antirenin drugs have relatively little effect.
2.3
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