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Renin release is differentially sensitive to clinically used calcineurin inhibitors
Author(s) -
Friis Ulla G,
Madsen Kirsten,
Skøtt Ole,
Hansen Pernille B,
Jensen Boye L
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.736.5
Subject(s) - calcineurin , juxtaglomerular apparatus , renin–angiotensin system , chemistry , protein kinase a , pharmacology , phosphatase , patch clamp , endocrinology , kinase , medicine , microbiology and biotechnology , biology , enzyme , biochemistry , receptor , transplantation , blood pressure
Renin release from juxtaglomerular cells (JG) is paradoxically inhibited by a rise in [Ca 2+ ] i . We hypothesized that the calmodulin‐dependent phosphatase calcineurin in necessary for the inhibitory effect of [Ca 2+ ] i . The hypothesis was tested in isolated JG‐cells by whole cell patch clamp and by renin release studies. In rat JG‐cells, the calcineurin inhibitor cyclosporine A (CsA, 5 μM) increased membrane capacitance (Cm), an index of cell surface area, in single JG‐cells by 10.7% ± 2.9% (n=5; P<0.05). A structurally distinct calcineurin inhibitor tacrolimus did not change C m significantly when applied directly to JG‐cells. Similarly, renin release from JG‐cell cultures was stimulated by cyclosporine but not tacrolimus. Binding proteins for both inhibitors were detected in afferent arterioles (cyclophilin and FKBP). The effect on Cm was mimicked by the calmodulin‐inhibitor W‐13 (100 μM) in the patch pipette. When the experiments were repeated with a protein kinase A‐blocker (RpcAMPs (5 μM)) in the patch pipette, CsA and W‐13 still increased Cm significantly (15.8 % ± 4.2 % (n = 4) and 9.3 ± 3% (n = 4), respectively) indicating that the increase in Cm is independent on the cAMP‐PKA pathway. We conclude that calcineurin exerts a tonic suppressor effect on renin release from juxtaglomerular cells and that renin release is differentially sensitive to clinically used calcineurin inhibitors. This study was supproted by grants from Carlsbergfondet, the Novo Nordisk Foundation and the Danish Heart Foundation.