The role of calcium in the regulation of renin secretion

Abstract

Renin is the enzyme which is the rate-limiting step in the formation of the hormone angiotensin II. Therefore, the regulation of renin secretion is critical in understanding the control of the renin-angiotensin-aldosterone system and its many biological and pathological actions. Renin is synthesized, stored in, and released from the juxtaglomerular (JG) cells of the kidney. While renin secretion is positively regulated by the "second messenger" cAMP, unlike most secretory cells, renin secretion from the JG cell is inversely related to the extracellular and intracellular calcium concentrations. This novel relationship is referred to as the "calcium paradox." This review will address observations made over the past 30 years regarding calcium and the regulation of renin secretion, and focus on recent observations which address this scientific conundrum. These include 1) receptor-mediated pathways for changing intracellular calcium; 2) the discovery of a calcium-inhibitable isoform of adenylyl cyclase associated with renin in the JG cells; 3) calcium-sensing receptors in the JG cells; 4) calcium-calmodulin-mediated signals; 5) the role of phosphodiesterases; and 6) connexins, gap junctions, calcium waves, and the cortical extracellular calcium environment. While cAMP is the dominant second messenger for renin secretion, calcium appears to modulate the integrated activities of the enzymes, which balance cAMP synthesis and degradation. Thus this review concludes that calcium modifies the amplitude of cAMP-mediated renin-signaling pathways. While calcium does not directly control renin secretion, increased calcium inhibits and decreased calcium amplifies cAMP-stimulated renin secretion.

Fig. 1.

Diagram of the anatomic juxtaposition of the juxtaglomerular apparatus, including the granular renin-containing juxtaglomerular (JG) cells, macula densa, and extraglomerular matrix with the glomerulus and its vascular pole.

Fig. 2.

Simplified schematic of calcium-mediated inhibition of adenylyl cyclase V and its effect on cAMP formation and the stimulation of active renin release from the granules (G) of the JG cell. The example uses the response of the calcium sensing receptor (CaSR) to interstitial calcium, but could be generalized for any agonist-G protein-coupled receptor interaction which increases intracellular calcium. The receptors act to release calcium from intracellular stores and/or by promoting calcium entry through various calcium channels (see text). Increased intracellular calcium diminishes the activity of adenylyl cyclase-V, thereby reducing the basal formation of cAMP as well as cAMP stimulated directly through PGE₂ activation of the EP4 receptor or renal sympathetic nerve stimulation (RSN) of β₁-adrenergic receptors. Formed cAMP can be modified further through its breakdown by phosphodiesterases (PDE).