Figure 1. Overview of the mechanisms involved in renin synthesis and release and the RAAS cascade.

Three major mechanisms control renin synthesis and release: (1) changes in perfusion pressure activate the renal baroreceptor, (2) β-adrenergic stimulation is triggered by local or circulating catecholamines via sympathetic nervous system activation, and (3) macula densa signaling via prostaglandin-E2 (PGE2) paracrine secretion in response to a reduction in NaCl concentration. Renin generates angiotensin I (Ang I) from angiotensinogen, which is then hydrolyzed by the angiotensin-converting enzyme (ACE) to produce angiotensin II (Ang II). Ang II is a potent direct vasoconstrictor that also stimulates adrenal release of aldosterone, which promotes Na⁺ tubular reabsorption. These combined actions of the RAAS are essential to maintain BP and fluid-electrolyte homeostasis. Within the renin cell, cAMP activates protein kinase A (PKA), which phosphorylates cAMP-responsive element-binding protein (Creb), which in turn binds the cAMP-responsive element (CRE) in the renin enhancer, and recruits histone acetyltransferases such as P300 resulting in epigenetic changes (H3K27ac) at the regulatory region of the renin gene, opening of chromatin and renin transcription. Activation of the Notch/ recombination signal binding protein for immunoglobulin kappa J region (Rbp-j) pathway also stimulates renin transcription. AC, adenylate cyclase; β-AR indicates beta-adrenergic receptor; COX2, cyclooxygenase-2; EP4R, Prostaglandin-E2 receptor 4; Gsα, activating G-protein–coupled subunit; NHE, Na⁺/H⁺ exchanger; NKCC2, Na⁺-K⁺−2Cl⁻ cotransporter; PGE2, prostaglandin E2.