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

Abstract

Ortiz-Capisano MC, Atchison DK, Harding P, Lasley RD, Beierwaltes WH. Adenosine inhibits renin release from juxtaglomerular cells via an A 1 receptor-TRPC-mediated pathway. Am J Physiol Renal Physiol 305: F1209 -F1219, 2013. First published July 24, 2013 doi:10.1152/ajprenal.00710.2012.-Renin is synthesized and released from juxtaglomerular (JG) cells. Adenosine inhibits renin release via an adenosine A 1 receptor (A1R) calcium-mediated pathway. How this occurs is unknown. In cardiomyocytes, adenosine increases intracellular calcium via transient receptor potential canonical (TRPC) channels. We hypothesized that adenosine inhibits renin release via A 1R activation, opening TRPC channels. However, higher concentrations of adenosine may stimulate renin release through A 2R activation. Using primary cultures of isolated mouse JG cells, immunolabeling demonstrated renin and A 1R in JG cells, but not A2R subtypes, although RT-PCR indicated the presence of mRNA of both A 2AR and A2BR. Incubating JG cells with increasing concentrations of adenosine decreased renin release. Different concentrations of the adenosine receptor agonist N-ethylcarboxamide adenosine (NECA) did not change renin. Activating A 1R with 0.5 M N6-cyclohexyladenosine (CHA) decreased basal renin release from 0.22 Ϯ 0.05 to 0.14 Ϯ 0.03 g of angiotensin I generated per milliliter of sample per hour of incubation (AngI/ml/mg prot) (P Ͻ 0.03), and higher concentrations also inhibited renin. Reducing extracellular calcium with EGTA increased renin release (0.35 Ϯ 0.08 g AngI/ml/mg prot; P Ͻ 0.01), and blocked renin inhibition by CHA (0.28 Ϯ 0.06 g AngI/ml/mg prot; P Ͻ 0. 005 vs. CHA alone). The intracellular calcium chelator BAPTA-AM increased renin release by 55%, and blocked the inhibitory effect of CHA. Repeating these experiments in JG cells from A 1R knockout mice using CHA or NECA demonstrated no effect on renin release. However, RT-PCR showed mRNA from TRPC isoforms 3 and 6 in isolated JG cells. Adding the TRPC blocker SKF-96365 reversed CHA-mediated inhibition of renin release. Thus A 1R activation results in a calcium-dependent inhibition of renin release via TRPC-mediated calcium entry, but A 2 receptors do not regulate renin release. renin; adenosine; calcium; A 1R; CHA; adenosine receptors; transient receptor potential canonical RENIN IS PRODUCED BY, STORED in, and released from juxtaglomerular (JG) cells located in the lamina media of the afferent arteriole at the entrance to the glomerulus (7, 31). Two main intracellular second-messenger systems are known to regulate renin secretion: stimulation of renin release by the cyclic nucleotide cAMP; and inhibition or renin secretion by increased intracellular calcium (1-3, 16, 25, 30).Adenosine is a purine nucleoside catabolite of ATP. Adenosine's effects are mediated by the activation of four G protein-coupled receptor (GPCR) subtypes: A 1 , A 2A , A 2B , and A 3 (13, 44). Adenosine inhibits renin secretion in vivo and in vitro (9, 37). It is considered that adenosine from the macula densa inhib...

Endothelin inhibits renin release from juxtaglomerular cells via endothelin receptors A and B via a transient receptor potential canonical-mediated pathway

“…To test the involvement of TRPC in the endothelin‐mediated inhibition of renin release, a nonselective TRPC inhibitor, SKF‐96365 (Ortiz‐Capisano et al. ), was used with incubation of JG cells with both ET‐1 and ET‐2 (see Fig. ).…”

“…Recently published data from this laboratory described TRPC 3 and 6 expression in isolated JG cells and their involvement in Ca‐mediated inhibition of renin release in an adenosine‐dependent system (Ortiz‐Capisano et al. ). TRPC1, TRPC4, and TRPC5, proposed to be possible candidate channels for SOCE (Liao et al.…”

“…Endothelin (ET) 1, via ETB receptors, could activate the phospholipase C (PLC)/IP3 signaling pathway, potentially stimulating store-operated Ca channels (Salido et al 2009). Recently published data from this laboratory described TRPC 3 and 6 expression in isolated JG cells and their involvement in Ca-mediated inhibition of renin release in an adenosine-dependent system (Ortiz-Capisano et al 2013a). TRPC1, TRPC4, and TRPC5, proposed to be possible candidate channels for SOCE (Liao et al 2008), might be expressed in JG cells as well.…”

Canonical Transient Receptor Potential 6 Channel: A New Target of Reactive Oxygen Species in Renal Physiology and Pathology

“…Ca 2+ plays an unusual role in the control of renin secretion from the renal JG cells in the way that an increase in the Ca 2+ concentration inhibits the exocytosis of renin. The transcript of TRPC6 was detected in mouse JG cells (149). TRPC6 might be responsible for adenosineevoked inhibition of renin release (149).…”

“…The transcript of TRPC6 was detected in mouse JG cells (149). TRPC6 might be responsible for adenosineevoked inhibition of renin release (149).…”