Inhibition of calcineurin phosphatase promotes exocytosis of renin from juxtaglomerular cells
To examine the role of the calcium/calmodulin-dependent phosphatase calcineurin in regulation of renin release, we assayed exocytosis using whole-cell patch clamp of single juxtaglomerular cells in culture. The calcineurin inhibitor, cyclosporine A (CsA), significantly increased juxtaglomerular cell membrane capacitance, an index of cell surface area and an established measure of exocytosis in single-cell assays. This effect was mimicked by intracellular delivery of a calcineurin inhibitory peptide, the calcium chelator ethylene glycol tetraacetic acid (EGTA), or the calmodulin inhibitor W-13. Simultaneous exposure to EGTA and CsA had no additive effect. The protein kinase A (PKA) blocker RpcAMPs had no effect on the CsA-induced increase in membrane capacitance. Intra-and extracellular application of tacrolimus did not alter membrane capacitance. A calmodulin antagonist (calmidazolium) and CsA, but not tacrolimus, significantly stimulated renin release from cultured juxtaglomerular cells. Juxtaglomerular cells expressed the calcineurin isoforms A-ß and A-gamm but not A-α. Plasma renin concentrations (PRCs) were not different in wild-type, calcineurin A-α, or A-ß knockout mice but increased after CsA treatment of the A-α knockout, while renin mRNA was suppressed. We conclude that calcineurin and calcium/calmodulin suppress exocytosis of renin from juxtaglomerular cells independent of PKA.
Madsen, K.; Friis, U. G.; Gooch, J. L.; Hansen, P. B.; Holmgaard, L.; Skatt, O.; and Jensen, B. L., "Inhibition of calcineurin phosphatase promotes exocytosis of renin from juxtaglomerular cells" (2010). PCOM Scholarly Papers. 497.
This article was published in Kidney international, Volume 77, Issue 2, Pages 110-117.The published version is available at http://dx.doi.org/10.1038/ki.2009.418.
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