Stimulation of the juxtaglomerular cell calcium-sensing receptor with cinacalcet decreased renin release, an effect that was reversed by selective PDE1 inhibitors.
PDE1C is expressed in juxtaglomerular cells and mediates calcium-induced inhibition of renin release by degrading cAMP.
Tasa de eventos absoluta: 0.38% vs 0.89%
valor p: p=<0.001
Renin release from the juxtaglomerular (JG) cell is stimulated by the second messenger cAMP and inhibited by calcium. We previously showed JG cells contain a calcium sensing receptor (CaSR), which, when stimulated, decreases cAMP formation and inhibits renin release. We hypothesize CaSR activation decreases cAMP and renin release, in part, by stimulating a calcium calmodulin-activated phosphodiesterase 1 (PDE1). We incubated our primary culture of JG cells with two selective PDE1 inhibitors 8-methoxymethil-IBMX (8-MM-IBMX; 20 microM) and vinpocetine (40 microM) and the calmodulin inhibitor W-7 (10 microM) and measured cAMP and renin release. Stimulation of the JG cell CaSR with the calcimimetic cinacalcet (1 microM) resulted in decreased cAMP from a basal of 1.13 +/- 0.14 to 0.69 +/- 0.08 pM/mg protein (P < 0.001) and in renin release from 0.89 +/- 0.16 to 0.38 +/- 0.08 microg ANG I/mlxh(-1)xmg protein(-1) (P < 0.001). However, the addition of 8-MM-IBMX with cinacalcet returned both cAMP (1.10 +/- 0.19 pM/mg protein) and renin (0.57 +/- 0.16 microg ANG I/mlxh(-1)xmg protein(-1)) to basal levels. Similar results were obtained with vinpocetine, and also with W-7. Combining 8-MM-IBMX and W-7 had no additive effect. To determine which PDE1 isoform is involved, we performed Western blot analysis for PDE1A, B, and C. Only Western blot analysis for PDE1C showed a characteristic band apparent at 80 kDa. Immunofluorescence showed cytoplasmic distribution of PDE1C and renin in the JG cells. In conclusion, PDE1C is expressed in isolated JG cells, and contributes to calcium's inhibitory modulation of renin release from JG cells.
Ortiz‐Capisano et al. (Thu,) conducted a other in Normal physiology (renin release). Cinacalcet followed by PDE1 inhibitors (8-MM-IBMX or vinpocetine) vs. Untreated controls (basal conditions) was evaluated on Renin release (µg ANG I/ml/h/mg protein) (p=<0.001). Stimulation of the juxtaglomerular cell calcium-sensing receptor with cinacalcet decreased renin release, an effect that was reversed by selective PDE1 inhibitors.
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