Prorenin as a reproductive hormone. New form of the renin system

doi:10.1016/0002-9343(86)90402-X

The American Journal of Medicine

Volume 81, Issue 6, December 1986, Pages 1041-1046

https://doi.org/10.1016/0002-9343(86)90402-X Get rights and content

Abstract

Prorenin, the biosynthetic precursor of renin, is synthesized by the kidneys. Herein is reviewed recent evidence that the ovaries also secrete prorenin. It was found that prorenin is present in mature human ovarian follicular fluid in extremely high concentrations and that plasma prorenin levels increase transiently in blood during the menstrual cycle at the time of ovulation. No change in plasma active renin levels occurs at this time. Plasma prorenin level also increases 10-fold in pregnant women very soon after conception. The ovaries are apparently the source of this rise, since plasma prorenin levels did not increase in a pregnant woman with ovarian failure who received a donor egg. All of these changes in plasma prorenin levels appear to be caused by gonadotropic hormones. These results suggest a role for ovarian prorenin in human reproductive function. They may have relevance to studies of female infertility, birth control, and toxemia of pregnancy. They also suggest that a renin system exists that is regulated by changes in prorenin.

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Cited by (82)

The (pro)renin receptor: A new addition to the renin-angiotensin system?
2008, European Journal of Pharmacology
Citation Excerpt :
Since the renin levels per gram tissue weight are often as high as or even higher than its levels in blood (Danser et al., 1994; Katz et al., 1997; Tada et al., 1992), the underlying uptake mechanism cannot be simple diffusion. Indeed, many years ago it was already suggested that renin ‘receptors’ exist (Loudon et al., 1983; Sealey et al., 1986), and subsequent data confirmed this view (Danser et al., 1994). Further speculation led to the concept that such a receptor might also bind prorenin (Danser and Deinum, 2005), and that this might facilitate its conversion to renin, e.g., following internalization of the prorenin-receptor complex.
The renin–angiotensin system is still incompletely understood. In particular, the function of prorenin, the inactive precursor of renin, is unknown. Yet, prorenin levels are > 10-fold higher than renin levels, and prorenin increases even further in subjects with diabetes mellitus displaying microvascular complications. The recent discovery of a (pro)renin binding receptor may shed light on the role of prorenin. This review discusses the possibility that prorenin binding to this receptor results in prorenin activation, thereby allowing angiotensin generation, and that prorenin simultaneously acts as an agonist of this receptor, inducing angiotensin-independent effects. Transgenic animals overexpressing the receptor, as well as a receptor antagonist are now available, and future studies should reveal to what degree this concept is applicable to humans as well.
Ovarian hyperstimulation syndrome: Aetiology, prevention and management
2006, Reviews in Gynaecological and Perinatal Practice
Ovarian hyperstimulation syndrome is a serious and potentially life-threatening complication of infertility treatment. The symptoms are generally triggered by human chorionic gonadotrophin (hCG) following ovulation induction in an in vitro fertilisation cycle. It is believed that the underlying pathology is a shift of protein-rich fluid from the intravascular space to extravascular compartments. The exact aetiology has not been established however it is felt that vascular permeability plays a key role which may be mediated by the immune system, VEGF and the ovarian rennin–angiotensin system. Prevention of the syndrome is important and involves monitoring of patients undergoing ovulation induction, modifying treatment regimens and pharmacological interventions. The management of patients depends upon the severity of the condition. There should be a low threshold for hospital admission where close monitoring, replacement of intravascular volume, thromboprophylaxis and paracentesis (if required) can be effected.
Human prorenin has "gate and handle" regions for its non-proteolytic activation
2003, Journal of Biological Chemistry
We investigated the mechanism for non-proteolytic activation of human prorenin using five kinds of antibodies. Each of the antigens, L^1PPTDTTTFKRI^11P, T^7PFKRIFLKRMP^17P, I^11PFLKRMPSIRESLKER^26P, M^16PPSIRESLKER^26P, and G^27PVDMARLGPEWSQPM^41P, was designed from the tertiary structure of predicted prorenin. These antibodies were labeled anti-01/06, anti-07/10, anti-11/26, anti-16/26, and anti-27/41, respectively, for their binding specificities. Inactive recombinant human prorenin (0.1 nM) bound to various concentrations of anti-01/06, anti-11/26, and anti-27/41 antibodies at 4 °C with equilibrium dissociation constants of 138, 41, and 22 nM, respectively. However, intact prorenin (0.1 nM) did not show significant binding to 200 nM anti-07/10 and anti-16/26 antibodies for 20 h. Ninety percent of prorenin (0.1 nM) was found to be non-proteolytically activated by incubation with anti-11/26 antibodies (200 nM) at 4 °C for 20 h. Prorenin was not active even under complex with either anti-01/06 or anti-27/41 antibodies. Prorenin was also reversibly activated at pH 3.3 and 4 °C for 25 h. The acid-activated prorenin bound to anti-07/10 and anti-16/26 antibodies as well as to anti-01/06, anti-11/15, and anti-27/41 antibodies at neutral pH and 4 °C in 2 h. Their dissociation constants were 13, 40, 8.6, 3.6, and 14 nM, respectively. The acid-activated prorenin was re-inactivated by incubation at pH 7.4 and 4 °C in 50 h. Anti-07/10 and anti-11/26 antibodies inhibited such re-inactivation at 25 °C by more than 90% and 50%, respectively, whereas other kinds of antibodies did not prevent the re-inactivation at 25 °C. These results indicate that prorenin has “gate” (T^7PFKR^10P) and “handle” (I^11PFLKR^15P) regions critical for its non-proteolytic activation.
The ovarian hyperstimulation syndrome
2000, Fertility and Sterility
Objective: To review the up-to-date literature concerning the pathogenesis of, risk factors for, prevention of, and therapy for the ovarian hyperstimulation syndrome, and to provide suggestions for management of this syndrome.
Design: Literature review combined with on-site clinical experiences at the authors’ institution of practice.
Patient(s): Women who have risk factors for or manifest the ovarian hyperstimulation syndrome.
Intervention(s): Intravenous fluid management, thrombosis prevention techniques, paracentesis techniques, and critical care management protocols.
Main Outcome Measure(s): Staging system of the ovarian hyperstimulation syndrome, criteria for outpatient versus hospitalization management, and indications for varying levels of interventional management.
Result(s): The ovarian hyperstimulation syndrome, unique to the field of assisted reproductive technology, remains a largely elusive and unpredictable iatrogenic physiologic complication in the course of pharmacologic ovarian stimulation. Reliable information on risk factors, possible physiologic mechanisms, prevention techniques, and management is fortunately progressing, and overall advances are being made in this field. The present review is an attempt to summarize the modern literature regarding this syndrome and to use this current knowledge to provide a basis for acceptable management regimens.
Conclusion(s): Ovarian hyperstimulation syndrome is a serious complication of assisted reproductive technology, with potential for critical morbidity and death. Physicians who prescribe medications known to be associated with this syndrome should be familiar with identifiable risk factors, means of prevention, and a system for staging and treating the disease and have a current knowledge base for putative models of pathogenesis.
The dominant role of the prosegment of prorenin in determining the rate of activation by acid or trypsin: Studies with molecular chimeras
2000, Biochemical and Biophysical Research Communications
Human prorenin activation by acid or trypsin is faster than rat prorenin by two orders of magnitude. No plausible mechanism exists to explain the difference. Two chimeric mutant prorenins were produced in CHO cells. A chimera, hPro/rRen, composed of human prorenin prosegment and rat active renin segment, was activated as fast as wild-type human prorenin at pH 3.3 and 25°C or by trypsin (1 μg/ml). The other chimera, rPro/hRen, composed of rat prorenin prosegment and human active renin segment, was activated as slowly as wild-type rat prorenin at pH 3.3 and 25°C or by trypsin (50 μg/ml). These results indicate that the rate of activation of prorenin is predominantly determined by the N-terminal pro-sequence. Plausible mechanisms are discussed.
The ovarian renin-angiotensin system in reproductive physiology
1997, Frontiers in Neuroendocrinology
The identification of the presence of prorenin, renin, angiotensinogen, angiotensin-converting enzyme, angiotensin II (Ang II), and Ang II receptors in the ovary suggests that there is a functional ovarian renin–angiotensin system (RAS). It could play a significant role in such areas of ovarian physiology as follicular development, steroidogenesis, oocyte maturation, ovulation, and follicle atresia. Expression of the ovarian RAS is regulated by gonadotropins. Ang II, a bioactive octapeptide of RAS, has important effects as a paracrine/autocrine regulator at different stages of the reproductive cycle. Ang II modulates ovarian steroidogenesis and formation of the corpus luteum and also stimulates oocyte maturation and ovulation via Ang II receptors on granulosa cells. In addition, increasing evidence demonstrates that Ang II is a major factor in regulating the function of atretic follicles. In any physiologic system, aberrations result in the development of pathologic states. Disturbances in the ovarian RAS can be the cause or the result of such reproductive disorders as polycystic ovary syndrome, ovarian hyperstimulation syndrome, ovarian tumors, and ectopic pregnancy. Data support the concept of an active and regulated RAS in ovarian follicles. Species differences observed in the expression of ovarian RAS suggest varying functional roles among species with respect to ovarian physiology.

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^☆: This work was supported by National Heart, Lung, and Blood Institute Grant HL-18323SCR from the National Institutes of Health.

¹: Dr. Itskovitz was on leave from the Department of Obstetrics and Gynecoogy, Rambam Medical Center, Haifa, Israel, at the time of this study.

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ReviewProrenin as a reproductive hormone. New form of the renin system☆

Abstract

Biochem Biophys Res Commun

Biochem Biophys Res Commun

Am J Obstet Gynecol

Am J Obstet Gynecol

Am J Obstet Gynecol

Fertil Steril

J Biol Chem

J Biol Chem

J Biol Chem

The renin-angiotensin-aldosterone hormonal system and regulation of sodium, potassium, and blood pressure homeostasis

Prorenin and other large molecular weight forms of renin

Endocr Rev

Prorenin

Biomed Res

Inactive renin: an attempt at a perspective

Clin Sci

Immunological identification of both plasma and human renal inactive renin as prorenin

J Clin Endocrinol Metab

Activation of renin in human amniotic fluid by low pH

Enzymologia

Human chorionic cells in primary culture: a model for renin biosynthesis

J Clin Endocrinol Metab

Release of inactive renin from human fetal membranes and isolate trophoblasts

Clin Exp Hypertens

Plasma prorenin and renin in anephric patients

Circ Res

An extrarenal source of “renin-like” activity in anephric man

Circ Res

Immunohistochemical evidence for renin in human endocrine tissues

J Clin Endocrinol Metab

Markedly elevated specific renin levels in the adrenal in genetically hypertensive rats

Review
Prorenin as a reproductive hormone. New form of the renin system☆