PGE2 induces COX-2 expression in podocytes via the EP4 receptor through a PKA-independent mechanism
Cyclooxygenase-2 (COX-2)-dependent prostaglandin E2 (PGE2) synthesis correlates with the onset of proteinuria and increased glomerular capillary pressure (Pgc) glomerular disease models. We previously showed that an in vitro surrogate for Pgc (cyclical mechanical stretch) upregulates the expression...
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2008
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| Online Access: | http://hdl.handle.net/10725/2318 http://dx.doi.org/10.1016/j.cellsig.2008.08.007 http://www.sciencedirect.com/science/article/pii/S0898656808002350 |
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| _version_ | 1864513457901010944 |
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| author | Faour, Wissam |
| author2 | Gomi, Kaede Kennedy, Christopher |
| author2_role | author author |
| author_facet | Faour, Wissam Gomi, Kaede Kennedy, Christopher |
| author_role | author |
| dc.creator.none.fl_str_mv | Faour, Wissam Gomi, Kaede Kennedy, Christopher |
| dc.date.none.fl_str_mv | 2008 2015-10-23T08:03:27Z 2015-10-23T08:03:27Z 2015-10-23 |
| dc.identifier.none.fl_str_mv | 0898-6568 http://hdl.handle.net/10725/2318 http://dx.doi.org/10.1016/j.cellsig.2008.08.007 Faour, W. H., Gomi, K., & Kennedy, C. R. (2008). PGE 2 induces COX-2 expression in podocytes via the EP 4 receptor through a PKA-independent mechanism. Cellular signalling, 20(11), 2156-2164. http://www.sciencedirect.com/science/article/pii/S0898656808002350 |
| dc.language.none.fl_str_mv | en |
| dc.relation.none.fl_str_mv | Cellular signalling |
| dc.rights.*.fl_str_mv | info:eu-repo/semantics/openAccess |
| dc.title.none.fl_str_mv | PGE2 induces COX-2 expression in podocytes via the EP4 receptor through a PKA-independent mechanism |
| dc.type.none.fl_str_mv | Article info:eu-repo/semantics/publishedVersion info:eu-repo/semantics/article |
| description | Cyclooxygenase-2 (COX-2)-dependent prostaglandin E2 (PGE2) synthesis correlates with the onset of proteinuria and increased glomerular capillary pressure (Pgc) glomerular disease models. We previously showed that an in vitro surrogate for Pgc (cyclical mechanical stretch) upregulates the expression of both COX-2 and the PGE2 responsive E-Prostanoid receptor, EP4 in cultured mouse podocytes. In the present study we further delineate the signaling pathways regulating podocyte COX-2 induction. Time course experiments carried out in conditionally-immortalized mouse podocytes revealed that PGE2 transiently increased phosphorylated p38 MAPK levels at 10 min, and induced COX-2 protein expression at 4 h. siRNA-mediated knockdown of EP4 receptor expression, unlike treatment with the EP1 receptor antagonist SC 19220, completely abrogated PGE2-induced p38 phosphorylation and COX-2 upregulation suggesting the involvement of the EP4 receptor subtype. PGE2-induced COX-2 induction was abrogated by inhibition of either p38 MAPK or AMP activated protein kinase (AMPK), and was mimicked by AICAR, a selective AMPK activator, and by the cAMP-elevating agents, forskolin (FSK) and IBMX. Surprisingly, neither PGE2 nor FSK/IBMX-dependent p38 activation and COX-2 expression were blocked by PKA inhibitors or mimicked by 8-cPT-cAMP a selective EPAC activator, but were instead abrogated by Compound C, suggesting the involvement of AMPK. These results indicate that in addition to mechanical stretch, PGE2 initiates a positive feedback loop in podocytes that drives p38 MAPK activity and COX-2 expression through a cAMP/AMPK-dependent, but PKA-independent signaling cascade. This PGE2-induced signaling network activated by increased Pgc could be detrimental to podocyte health and glomerular filtration barrier integrity. |
| eu_rights_str_mv | openAccess |
| format | article |
| id | LAURepo_1f8490b362e2e719a8dc1877c5003cc3 |
| identifier_str_mv | 0898-6568 Faour, W. H., Gomi, K., & Kennedy, C. R. (2008). PGE 2 induces COX-2 expression in podocytes via the EP 4 receptor through a PKA-independent mechanism. Cellular signalling, 20(11), 2156-2164. |
| language_invalid_str_mv | en |
| network_acronym_str | LAURepo |
| network_name_str | Lebanese American University repository |
| oai_identifier_str | oai:laur.lau.edu.lb:10725/2318 |
| publishDate | 2008 |
| repository.mail.fl_str_mv | |
| repository.name.fl_str_mv | |
| repository_id_str | |
| spelling | PGE2 induces COX-2 expression in podocytes via the EP4 receptor through a PKA-independent mechanismFaour, WissamGomi, KaedeKennedy, ChristopherCyclooxygenase-2 (COX-2)-dependent prostaglandin E2 (PGE2) synthesis correlates with the onset of proteinuria and increased glomerular capillary pressure (Pgc) glomerular disease models. We previously showed that an in vitro surrogate for Pgc (cyclical mechanical stretch) upregulates the expression of both COX-2 and the PGE2 responsive E-Prostanoid receptor, EP4 in cultured mouse podocytes. In the present study we further delineate the signaling pathways regulating podocyte COX-2 induction. Time course experiments carried out in conditionally-immortalized mouse podocytes revealed that PGE2 transiently increased phosphorylated p38 MAPK levels at 10 min, and induced COX-2 protein expression at 4 h. siRNA-mediated knockdown of EP4 receptor expression, unlike treatment with the EP1 receptor antagonist SC 19220, completely abrogated PGE2-induced p38 phosphorylation and COX-2 upregulation suggesting the involvement of the EP4 receptor subtype. PGE2-induced COX-2 induction was abrogated by inhibition of either p38 MAPK or AMP activated protein kinase (AMPK), and was mimicked by AICAR, a selective AMPK activator, and by the cAMP-elevating agents, forskolin (FSK) and IBMX. Surprisingly, neither PGE2 nor FSK/IBMX-dependent p38 activation and COX-2 expression were blocked by PKA inhibitors or mimicked by 8-cPT-cAMP a selective EPAC activator, but were instead abrogated by Compound C, suggesting the involvement of AMPK. These results indicate that in addition to mechanical stretch, PGE2 initiates a positive feedback loop in podocytes that drives p38 MAPK activity and COX-2 expression through a cAMP/AMPK-dependent, but PKA-independent signaling cascade. This PGE2-induced signaling network activated by increased Pgc could be detrimental to podocyte health and glomerular filtration barrier integrity.PublishedN/A2015-10-23T08:03:27Z2015-10-23T08:03:27Z20082015-10-23Articleinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/article0898-6568http://hdl.handle.net/10725/2318http://dx.doi.org/10.1016/j.cellsig.2008.08.007Faour, W. H., Gomi, K., & Kennedy, C. R. (2008). PGE 2 induces COX-2 expression in podocytes via the EP 4 receptor through a PKA-independent mechanism. Cellular signalling, 20(11), 2156-2164.http://www.sciencedirect.com/science/article/pii/S0898656808002350enCellular signallinginfo:eu-repo/semantics/openAccessoai:laur.lau.edu.lb:10725/23182019-02-28T10:12:23Z |
| spellingShingle | PGE2 induces COX-2 expression in podocytes via the EP4 receptor through a PKA-independent mechanism Faour, Wissam |
| status_str | publishedVersion |
| title | PGE2 induces COX-2 expression in podocytes via the EP4 receptor through a PKA-independent mechanism |
| title_full | PGE2 induces COX-2 expression in podocytes via the EP4 receptor through a PKA-independent mechanism |
| title_fullStr | PGE2 induces COX-2 expression in podocytes via the EP4 receptor through a PKA-independent mechanism |
| title_full_unstemmed | PGE2 induces COX-2 expression in podocytes via the EP4 receptor through a PKA-independent mechanism |
| title_short | PGE2 induces COX-2 expression in podocytes via the EP4 receptor through a PKA-independent mechanism |
| title_sort | PGE2 induces COX-2 expression in podocytes via the EP4 receptor through a PKA-independent mechanism |
| url | http://hdl.handle.net/10725/2318 http://dx.doi.org/10.1016/j.cellsig.2008.08.007 http://www.sciencedirect.com/science/article/pii/S0898656808002350 |