The major determinant of the rate of AngII production is the amount of renin released by the kidney. Renin is an aspartyl protease whose principal natural substrate is the circulating a2-globulin, angiotensinogen, secreted by hepatocytes. Renin is synthesized as a preproenzyme of 406 amino acid residues and processed to prorenin, a mature but inactive form. Prorenin then is activated by proteolytic cleavage to yield the active 340-amino acid renin. Both renin and prorenin are stored in the juxtaglomerular (j-g) cells and, after release, circulate in the blood. The concentration of prorenin in the circulation is approximately tenfold greater than that of the active enzyme. The t/2 of circulating renin is ~15 minutes.
Renin secretion from j-g cells is controlled predominantly by three pathways: two acting locally within the kidney, the third acting through the CNS and mediated by norepinephrine (NE) release from renal nerves (Figure 30—2). One intrarenal mechanism controlling renin release is the macula densa pathway (top of Figure 30—2A). Increased NaCl reabsorption and flux across the macula densa inhibits, while decreased NaCl flux stimulates, renin release. Both adenosine and prostaglandins mediate the macula densa pathway; the former is released when Na+ transport increases, and the latter is released when NaCl transport decreases. Adenosine, acting via the A1 adenosine receptor, inhibits renin release, while prostaglandins stimulate renin release. Inducible cyclooxygenase (COX-2) and neuronal nitric oxide synthase (nNOS) also play a role in macula densa—stimulated renin release. Figure 30—2B summarizes possible mechanisms regulating renin release.
Although a change in NaCl transport is a key modulator, regulation of the macula densa pathway pathway depends more on the luminal concentration of Cl- than Na+. Physiological changes in Cl- concentrations (e.g., from 20 to 60 mEq/L) at the macula densa profoundly affect macula densa-mediated renin release.
The second intrarenal mechanism controlling renin release is the intrarenal baroreceptor pathway (middle of Figure 30-2A). Increases and decreases in blood pressure in the preglomerular vessels inhibit and stimulate renin release, respectively. The immediate stimulus to secretion is believed to be reduced tension within the wall of the afferent arteriole. Changes in renal prostaglandins may partly mediate the intrarenal baroreceptor pathway, as may biomechanical coupling via stretch-activated ion channels.
The third mechanism, the b adrenergic receptor pathway (bottom of Figure 30-2A), is mediated by the release of NE from postganglionic sympathetic nerves; activation of b1 receptors on juxtaglomerular cells enhances renin secretion.
Increased renin secretion enhances the formation of AngII, which stimulates angiotensin subtype 1 (AT1) receptors on j-g cells to inhibit renin release, an effect termed short-loop negative feedback. AngII also increases arterial blood pressure via AT1 receptors. Increases in blood pressure inhibit renin release by (1) activating high-pressure baroreceptors and reducing renal sympathetic tone, (2) increasing pressure in the preglomerular vessels, and (3) reducing NaCl reabsorption in the proximal tubule, which increases tubular delivery of NaCl to the macula densa. The inhibition of renin release by AngII-induced increases in blood pressure has been termed long-loop negative feedback.
The physiological pathways regulating renin release can be influenced by blood pressure, salt intake, and a number of drugs. In all these cases, renin release is affected by the interplay of mechanisms summarized in Figure 30-2A. Loop diuretics (see Chapter 28) stimulate renin release in part by blocking NaCl reabsorption at the macula densa. Nonsteroidal anti-inflammatory drugs (NSAIDs) (see Chapter 26) inhibit prostaglandin synthesis and thereby decrease renin release. ACE inhibitors, angiotensin receptor blockers (ARBs), and renin inhibitors interrupt both the short- and long-loop negative feedback mechanisms and therefore increase renin release. Chronic administration of ACE inhibitors up-regulates renal COX-2 and nNOS expression. In general, diuretics and vasodilators increase renin release by decreasing arterial blood pressure. Centrally acting sympatholytic drugs and b adrenergic receptor antagonists decrease renin secretion by
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