Modulation Of Renin Secretion By Renal Cortical Interstitial Calcium

Renin is secreted from the juxtaglomerular (JG) cells of the afferent arteriole of the kidney, and is the rate-limiting enzyme of the renin-angiotensin system. Renin is quantified in vivo as plasma renin activity (PRA). Acutely elevating plasma calcium decreases PRA, but the mechanisms by which this occurs is unknown. The overall goal of our study was to determine how elevated plasma calcium decreases PRA. The calcium-sensing receptor (CaSR) is a ubiquitously expressed receptor that translates changes in plasma calcium into changes in intracellular signaling. JG cells are basolaterally bordered by the renal cortical interstitium, and parathyroid hormone (PTH) positively regulates the concentration of calcium in the renal interstitium. Thus, we hypothesized that hypercalcemia inhibits PRA via PTH-mediated increases in renal cortical interstitial Ca that act on the CaSR triggering Ca-mediated inhibition of renin secretion. We demonstrated that the CaSR is expressed in JG cells in vivo. Additionally, we demonstrated that acutely stimulating the CaSR with pharmacological agonists decrease basal and stimulated PRA in anesthetized rats in parathyroid-intact and parathyroidectomized (PTX) rats. We demonstrated that acute hypercalcemia decreased PRA, and that this inhibition of PRA is blocked by pharmacological CaSR antagonists and by PTX. Acute supplementation of PTH did not affect the inhibition of PRA by high calcium. Acute hypercalcemia increased renal cortical interstitial calcium, and this effect was blocked by PTX. This was likely due to decreased expression of the PTH-sensitive distal tubule calcium transporter TRPV5. Lastly, we demonstrated that increasing renal sodium chloride delivery failed to increase renal cortical interstitial calcium, and that inhibiting thick ascending limb sodium chloride reabsorption with Furosemide increased PRA without effecting major changes in renal cortical interstitial calcium. Our data support the notion that hypercalcemia inhibits PRA via PTH-mediated increases in renal cortical interstitial Ca that act on the CaSR