Active renin in the circulation originates in the kidneys and disappears entirely after nephrectomy. Within the kidney, renin is synthesized and stored in the juxtaglomerular apparatus of the nephron. Specialized granular cells called juxtaglomerular cells are the site of synthesis, storage, and release of renin. The macula densa is a specialized segment of the nephron that is closely associated with the vascular components of the juxtaglomerular apparatus. The vascular and tubular components of the juxtaglomerular apparatus, including the juxtaglomerular cells, are innervated by the sympathetic nervous system.
Prorenin is present in the circulation at levels higher than those of active renin. Plasma prorenin levels decrease after nephrectomy, but significant amounts remain. The remaining prorenin is thought to originate in extrarenal tissues including the adrenal gland, ovaries, testes, placenta, and retina. Plasma prorenin may exert actions via a unique prorenin receptor.
Control of Renin Release
The rate at which renin is released by the kidneys is the primary determinant of activity of the renin-angiotensin system.
Active renin is released by exocytosis immediately upon stimulation of the juxtaglomerular apparatus. Prorenin is released constitutively, usually at a rate higher than that of active renin, thus accounting for the fact that prorenin can constitute 80–90% of the total renin in the circulation. The significance of circulating prorenin and a unique prorenin receptor is discussed at the end of this section. Active renin release is controlled by a variety of factors, including the macula densa, a renal vascular receptor, the sympathetic nervous system, and ANG II.
A. Macula Densa
Renin release is controlled in part by the macula densa, a structure that has a close anatomic association with the afferent arteriole. The initial step involves the detection of some function of NaCl concentration in, or delivery to, the distal tubule, possibly by the Na+/K+/2Cl− cotransporter. The macula densa then signals changes in renin release by the juxtaglomerular cells such that there is an inverse relationship between NaCl delivery or concentration and renin release. Potential candidates for signal transmission include prostaglandin E2 (PGE2) and nitric oxide, which stimulate renin release, and adenosine, which inhibits it. Because the sodium intake in the general population is high, macula densa-mediated renin secretion is usually at basal levels, increasing only when sodium intake decreases.
B. Renal Baroreceptor
The renal vascular baroreceptor mediates an inverse relationship between renal artery pressure and renin release. The mechanism is not completely understood, but it appears that the juxtaglomerular cells are sensitive to stretch and that increased stretch results in decreased renin release. The decrease may result from influx of calcium which, somewhat paradoxically, inhibits renin release. The paracrine factors PGE2, nitric oxide, and adenosine have also been implicated in the baroreceptor control of renin release. At normal blood pressure, renal baroreceptor-mediated renin secretion is low; it increases in hypotensive states.
C. Sympathetic Nervous System
Norepinephrine released from renal sympathetic nerves stimulates renin release indirectly by α-adrenergic activation of the renal baroreceptor and macula densa mechanisms, and directly by an action on the juxtaglomerular cells. In humans, the direct effect is mediated by β1 adrenoceptors. Through this mechanism, reflex activation of the sympathetic nervous system by hypotension or hypovolemia leads to activation of the renin-angiotensin system.
D. Angiotensin