PubMed · 15259177
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Michael O'Leary, Bazian Ltd. 2002. Erectile dysfunction.. https://pubmed.ncbi.nlm.nih.gov/15259177/
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The Na,K-ATPase is a transmembrane protein responsible for maintaining electrochemical gradients across the plasma membrane in all mammalian cells, a process that is subject to regulation at the transcriptional as well as post-transcriptional level. Included among physiologic regulators in the kidney are prostaglandins. Previously, we demonstrated that prostaglandin E(1) (PGE(1)) increases the activity and expression of the Na,K-ATPase in Madin-Darby canine kidney cells (Taub, M., Borsick, M., Geisel, J., Matlhagela, K., Rajkhowa, T., and Allen, C. (2004) Exp. Cell Res. 299, 1-14; Taub, M. L., Wang, Y., Yang, I. S., Fiorella, P., and Lee, S. M. (1992) J. Cell. Physiol. 151, 337-346). In this work, we present evidence that transcription of the Na,K-ATPase beta(1) subunit is stimulated by PGE(1), an effect that may be mediated through the cAMP and Ca(2+) pathways. Transient transfection studies using 5'-deletion mutants of the human beta(1) subunit promoter indicated that region -100 to -92 containing the sequence AGTCCCTGC (a prostaglandin-responsive element (PGRE)) is required to elicit the stimulatory effects of PGE(1), 8-bromo-cAMP, phorbol 12-myristate 13-acetate, and okadaic acid. Electrophoretic mobility shift assays indicated that both the cAMP regulatory element-binding protein (CREB) and Sp1 bind to the PGRE present within this region of the beta(1) subunit promoter. The involvement of the PGRE and Sp1 sites in regulation by PGE(1) was further confirmed by the increased PGE(1) stimulation that was observed following insertion of the PGRE into a promoter/luciferase construct containing a portion of a heterologous promoter and the fibronectin promoter with four GC boxes. Further evidence suggesting an interaction between Sp1 and CREB was obtained from experiments conducted with pLuc-MCS-beta 72-167, which contains region -167 to -72 in the human beta(1) subunit promoter. The PGE(1) stimulation observed in Madin-Darby canine kidney cells transiently transfected with pLuc-MCS-beta 72-167 was reduced when the two GC boxes immediately upstream from the PGRE were translocated farther upstream. Also consistent with an interaction between CREB and Sp1 are the results of our immunoprecipitation studies indicating that CREB co-immunoprecipitated with Sp1 when an antibody against CREB, Sp1, or the CREB-binding protein was used.
The roles of prostaglandins (PGs) as mediators of inflammation have been extensively studied, and production of PGI2 and PGE2 at inflammatory sites has been reported. However, it has not yet been clarified which type of PG receptors has a major role in inflammatory exudation. To examine in vivo role of PG receptors in inflammatory exudation, we induced pleurisy in PG receptors (IP, EP1, EP2, EP3, or EP4) knockout mice by intrapleural injection of carrageenin. Pleural exudate accumulation in wild-type (WT) mice at 1 to 5 h, but not at 24 h, was significantly attenuated by the pretreatment with indomethacin, indicating that PGs are responsible for exudate formation at the early phase of pleurisy. Pleural exudation at 1 to 5 h in IP, EP2, or EP3 knockout mice, but not in EP1 and EP4 knockout, was significantly reduced compared with in WT mice. In the exudates, 6-keto-PGF1alpha and PGE2 were detected as the major PGs, each with its peak concentration at 3 h. In addition, involvement of bradykinin in the phenomenon was suggested by the fact that captopril, a kininase inhibitor, enhanced the exudate formation and increased the amount of 6-keto-PGF1alpha and PGE2 and that a bradykinin B2-receptor antagonist inhibited the exudate formation. In contrast, leukocyte migration into pleural cavity was not influenced by indomethacin-treatment nor by these receptor deficiencies. These results demonstrate participation of EP2 and EP3 along with IP in pleural exudate formation but not in leukocyte migration in carrageenin-induced mouse pleurisy.
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