Juxtaglomerular cell CaSR stimulation decreases renin release via activation of the PLC/IP3 pathway and the ryanodine receptor

• Published in: American journal of physiology. Renal physiology 2013-02, Vol.304 (3), p.F248-F256
• Main Authors: Ortiz-Capisano, M. Cecilia, Reddy, Mahendranath, Mendez, Mariela, Garvin, Jeffrey L., Beierwaltes, William H.
• Format: Article
• Language: English
• ISSN: 1931-857X; 1522-1466
• DOI: 10.1152/ajprenal.00451.2012

The calcium-sensing receptor (CaSR) is a G-coupled protein expressed in renal juxtaglomerular (JG) cells. Its activation stimulates calcium-mediated decreases in cAMP content and inhibits renin release. The postreceptor pathway for the CaSR in JG cells is unknown. In parathyroids, CaSR acts through G q and/or G i . Activation of G q stimulates phospholipase C (PLC), and inositol 1,4,5-trisphosphate (IP 3 ), releasing calcium from intracellular stores. G i stimulation inhibits cAMP formation. In afferent arterioles, the ryanodine receptor (RyR) enhances release of stored calcium. We hypothesized JG cell CaSR activation inhibits renin via the PLC/IP 3 and also RyR activation, increasing intracellular calcium, suppressing cAMP formation, and inhibiting renin release. Renin release from primary cultures of isolated mouse JG cells ( n = 10) was measured. The CaSR agonist cinacalcet decreased renin release 56 ± 7% of control ( P < 0.001), while the PLC inhibitor U73122 reversed cinacalcet inhibition of renin (104 ± 11% of control). The IP 3 inhibitor 2-APB also reversed inhibition of renin from 56 ± 6 to 104 ± 11% of control ( P < 0.001). JG cells were positively labeled for RyR, and blocking RyR reversed CaSR-mediated inhibition of renin from 61 ± 8 to 118 ± 22% of control ( P < 0.01). Combining inhibition of IP 3 and RyR was not additive. G i inhibition with pertussis toxin plus cinacalcet did not reverse renin inhibition (65 ± 12 to 41 ± 8% of control, P < 0.001). We conclude stimulating JG cell CaSR activates G q , initiating the PLC/IP 3 pathway, activating RyR, increasing intracellular calcium, and resulting in calcium-mediated renin inhibition.