PRORENIN AND RENIN AS SEPARATE MEDIATORS OF TISSUE AND CIRCULATING SYSTEMS

The renin gene is expressed in extrarenal tissues. High concentrations of renin occur in female reproductive organs: the adrenals of rats and mice have intermediate levels. The testis also synthesizes renin, as does the anterior pituitary. In contrast, very low levels of renin (ie, below plasma levels) are found in the heart and extrarenal vascular tissues. The predominal form of renin in the human ovary, placenta, and uterus is prorenin and the human ovary, testis, and adrenals have been shown to secrete prorenin into the circulation. The kidney is the only organ that secretes active renin and it is also the major source of plasma prorenin. We have used the ovary as a model to study extrarenal renin. Ovarian prorenin secretion changes dynamically during the menstrual cycle and during gerstation. Secretion occurs during the LH surge and when hCG is present in the blood during pregnancy. Plasma active renin does not change concurrently and only low levels of active renin are found in association with very high concentrations of prorenin in ovarian follicular fluid after gonadotropin stimulation. To explain the preponderance of prorenin stimulation. To explain the preponderance of prorenin, and the virtual absence of renin in the ovary we hypothesize that prorenin need not to be converted to active renin to have effect. In vitro, when prorenin is acidified to pH 3.3 or cooled to 0°C, it developes intrinsic catalytic activity without cleavage of the prosegment. Therefore we think that, in vivo, prorenin could be reversibly activated during binding to a specific receptor and be responsible for initiating the cascade of events that leads to localized angiotensin formation. It seems likely that there are two separate forms of the renin-angiotensin system: (1) The classical form is the circulating system, the activity of which depends on the regulated secretion of renin from the kidney. Its function is to maintain blood pressure and sodium and potassium homeostasis via angiotensin II and aldosterone actions. This circulating renin may also be taken up by vascular tissues where it could have an additional localized effect. (2) There also may be separate prorenin-angiotensin systems that function locally within reproductive organs whose role has yet to be fully defined. Definite studies are needed to determine whether or not there are also independent renin systems in the heart and vascular tree. The evidence for extrarenal vascular renin is not convincing and whereas renin mRNA has been found in the heart, renin's presence has not been conclusively demonstrated. A prorenin-angiotensin system may function within the kidney and coordinate with the circulating renal pressor system in the regulation of fluid and electrolyte hemeostasis.