Acute activation of the calcium-sensing receptor inhibits plasma renin activity in vivo

Abstract

In vitro, the renin-secreting juxtaglomerular cells express the calcium-sensing receptor, and its activation with the calcimimetic cinacalcet inhibits renin release. To test whether the activation of calcium-sensing receptor similarly inhibits plasma renin activity (PRA) in vivo, we hypothesized that the calcium-sensing receptor is expressed in juxtaglomerular cells in vivo, and acutely administered cinacalcet would inhibit renin activity in anesthetized rats. Since cinacalcet inhibits parathyroid hormone, which may stimulate renin activity, we sought to determine whether cinacalcet inhibits renin activity by decreasing parathyroid hormone. Lastly, we hypothesized that chronically administered cinacalcet would inhibit basal and stimulated renin in conscious rats. Calcium-sensing receptors and renin were localized in the same juxtaglomerular cells using immunofluorescence in rat cortical slices fixed in vivo. Cinacalcet was administered acutely via intravenous bolus in anesthetized rats and chronically in conscious rats by oral gavage. Acute administration of cinacalcet decreased basal renin activity from 13.6 ± 2.4 to 6.1 ± 1.1 ng ANG I·ml(-1)·h(-1) (P < 0.001). Likewise, cinacalcet decreased furosemide-stimulated renin from 30.6 ± 2.3 to 21.3 ± 2.3 ng ANG I·ml(-1)·h(-1) (P < 0.001). In parathyroidectomized rats, cinacalcet decreased renin activity from 9.3 ± 1.3 to 5.2 ± 0.5 ng ANG I·ml(-1)·h(-1) (P < 0.05) similar to sham-operated controls (13.5 ± 2.2 to 6.6 ± 0.8 ng ANG I·ml(-1)·h(-1), P < 0.05). Chronic administration of cinacalcet over 7 days had no significant effect on PRA under basal or stimulated conditions. In conclusion, calcium-sensing receptors are expressed in juxtaglomerular cells in vivo, and acute activation of these receptors with cinacalcet inhibits PRA in anesthetized rats, independent of parathyroid hormone.

Juxtaglomerular cell CaSR stimulation decreases renin release via activation of the PLC/IP3pathway and the ryanodine receptor

“…Thus increased intracellular calcium leads to suppression of synthesis and enhanced degradation of cAMP, the dominant cyclic nucleotide second messenger regulating renin secretion (20,36). Previous studies describing the calcium-mediated regulation of both cAMP and renin (6,32,(43)(44)(45)(46) are consistent with this model of the CaSR regulating intracellular calcium. To this we now describe that the PLC/IP 3 pathway is the critical postreceptor means by which this happens.…”

“…It is clear that calcium-mediated inhibition of renin by vasoconstrictors like angiotensin II, acting through the AT-1 receptor, plays a direct role in sodium homeostasis and blood pressure control (reviewed in 4 and 11). However, recent data from our laboratories (5,6) suggest the CaSR on the JG cell is coupled to PTH-mediated distal tubular calcium reabsorption. The renal cortical interstitium serves as the medium to which the CaSR on the JG cell responds in vivo (5).…”

“…Our data with the CaSR blocker Ronacaleret confirm that the calcium-mediated signaling we report is in fact due to activation of the CaSR, as blocking the CaSR completely eliminated calciummediated inhibition of renin release. We have previously described the CaSR on JG cells as a conduit linking the calcium concentration in the extracellular renal cortical interstitium to the intracellular concentrations as a pathway to regulate renin release (6,44). This occurs through increasing intracellular calcium, which suppresses the activity of the calcium-inhibitable adenylyl cyclase isoform-5 (45), possibly also isoform-6 (32), and also by activating the calcium-stimulated phosphodiesterase 1C (43).…”

“…We have previously reported, both in vitro (44) and in vivo (6), that the JG cells contain CaSR, and that increased media calcium or activation of the CaSR with a calcimimetic (6,43,44) leads to suppression of renin secretion. JG cells synthesize, store, and release renin, the rate-limiting enzyme involved in the formation of angiotensin II (9).…”

Adenosine inhibits renin release from juxtaglomerular cells via an A1 receptor-TRPC-mediated pathway

“…RT-PCR for TRPC 3,6, and 7 in JG cells. RT-PCR was used to examine the expression of the TRPC3/6/7 isoforms using pipetteselected isolated mouse JG cells.…”