PGE 2 reduces arachidonic acid release in murine podocytes: evidence for an autocrine feedback loop

• Published in: American Journal of Physiology: Cell Physiology 2003-02, Vol.284 (2), p.C302-C309
• Main Authors: Lemieux, Lyne I., Rahal, Sherine S., Kennedy, Chris R. J.
• Format: Article
• Language: English
• ISSN: 0363-6143; 1522-1563
• DOI: 10.1152/ajpcell.00024.2002

Increased glomerular prostaglandin E 2 (PGE 2 ) production is associated with the progression of diseases such as membranous nephropathy, nephrotic syndrome, and anti-Thy1 nephritis. We investigated the signaling pathways that regulate the synthesis and actions of PGE 2 in glomerular podocytes. To study its actions, we assessed the ability of PGE 2 to regulate the production of its own precursor, arachidonic acid (AA), in a mouse podocyte cell line. PGE 2 dose-dependently reduced phorbol ester (PMA)-mediated AA release. Inhibition of PMA-stimulated AA release by PGE 2 was found to be cAMP/PKA-dependent, because PGE 2 significantly increased levels of this second messenger, whereas the inhibitory actions of PGE 2 were reversed by PKA inhibition and reproduced by the cAMP-elevating agents forskolin and IBMX. PGE 2 synthesis in this podocyte cell line increased fourfold at 60 min in response to PMA, coinciding with upregulation of cyclooxygenase (COX)-2 but not COX-1 levels. However, PGE 2 synthesis was significantly reduced by COX-1-selective inhibition, yet to a lesser extent by COX-2-selective inhibition. Our findings suggest that PMA-stimulated PGE 2 synthesis in mouse podocytes requires both basal COX-1 activity and induced COX-2 expression, and that PGE 2 reduces PMA-stimulated AA release in a cAMP/PKA-dependent manner. Such an autocrine regulatory loop might have important consequences for podocyte and glomerular function in the context of renal diseases involving PGE 2 synthesis.