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Pharmacological Interventions Physiological interrelationships Major pathways modulating renin rc

B Macula Densa Cell Juxtaglomerular Cell

chronic sodium depletion

FIGURE 30-2 A. Schematic portrayal of the three major physiological pathways regulating renin release. See text for details. MD, macula densa; PGI2/PGE2 prostaglandins ^ and E2; NSAIDs, nonsteroidal anti-inflammatory drugs; Angll, angiotensin II; ACE, angiotensin-converting enzyme, ATj R, angiotensin subtype 1 receptor; NE/Epi, norepinephrine/ epinephrine; JGCs, juxtaglomerular cells. B. Possible mechanisms by which the macula densa regulates renin release. Both acute changes in tubular delivery of NaCl to the macula densa and chronic changes in dietary sodium intake cause appropriate signals to be conveyed from macula densa to the juxtaglomerular cells. Chronic sodium depletion up-regulates neuronal nitric oxide synthase (nNOS) and inducible cyclooxygenase (COX-2) in the macula densa. nNOS increases nitric oxide (NO) production, and NO reacts with superoxide anion (O2-) to form peroxynitrite, an activator of COX-2. In addition, COX-2 may be rapidly, although indirectly, inhibited and stimulated by increases and decreases in NaCl transport, respectively, across the macula densa. Arachidonic acid (AA) is converted to prostaglandins (PGs), which diffuse to nearby juxtaglomerular cells to stimulate adenylyl cyclase (AC) via prostaglandin receptors, such as EP4 and IP, that couple to Gs. Circulating and locally released catecholamines also stimulate adenylyl cyclase via bi receptors. Cyclic AMP (cAMP) augments renin release. Increased NaCl transport depletes ATP and increases adenosine (ADO) levels in the macula densa. ADO diffuses to the juxtaglomerular cells and activates the AT^Gi pathway, inhibiting AC and reducing cellular cAMP. Increased NaCl transport in the macula densa augments the efflux of ATP through basolateral maxi-anion channels, and ATP is converted to adenosine in the extracellular compartment and inhibits adenylyl cyclase via Ai receptors. In addition, ATP released from the macula densa may inhibit renin release directly by binding to P2Y receptors coupled to Gq on juxtaglomerular cells. Activation of Gq increases intracellular Ca2+, which inhibits renin release. Circulating AngII binds to ATi receptors on juxtaglomerular cells and inhibits renin release via Gq-induced increases in intracellular Ca2+.

reducing activation of ß adrenergic receptors on j-g cells. Phosphodiesterase inhibitors stimulate renin release by increasing cyclic AMP in j-g cells.

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