1. Antagonism of the prostaglandin E2 EP1 receptor in MDCK cells increases growth through activation of Akt and the epidermal growth factor receptor.
- Author
-
Taub M, Parker R, Mathivanan P, Ariff MA, and Rudra T
- Subjects
- Animals, Bridged Bicyclo Compounds pharmacology, Caproates pharmacology, Cell Proliferation drug effects, Dogs, ErbB Receptors antagonists & inhibitors, ErbB Receptors drug effects, Heterocyclic Compounds, 3-Ring pharmacology, Hydrazines pharmacology, Ibuprofen pharmacology, Kidney drug effects, Kidney physiology, Madin Darby Canine Kidney Cells, Oxazepines pharmacology, Proto-Oncogene Proteins c-akt antagonists & inhibitors, Proto-Oncogene Proteins c-akt drug effects, Quinazolines pharmacology, Receptors, Prostaglandin E, EP1 Subtype drug effects, Receptors, Prostaglandin E, EP1 Subtype physiology, Receptors, Prostaglandin E, EP2 Subtype physiology, Receptors, Prostaglandin E, EP4 Subtype physiology, Tyrphostins pharmacology, Cell Proliferation physiology, ErbB Receptors physiology, Kidney pathology, Proto-Oncogene Proteins c-akt physiology, Receptors, Prostaglandin E, EP1 Subtype antagonists & inhibitors, Signal Transduction physiology
- Abstract
The actions of prostaglandin E2 (PGE2) in the kidney are mediated by G protein-coupled E-prostanoid (EP) receptors, which affect renal growth and function. This report examines the role of EP receptors in mediating the effects of PGE2 on Madin-Darby canine kidney (MDCK) cell growth. The results indicate that activation of Gs-coupled EP2 and EP4 by PGE2 results in increased growth, while EP1 activation is growth inhibitory. Indeed, two EP1 antagonists (ONO-8711 and SC51089) stimulate, rather than inhibit, MDCK cell growth, an effect that is lost following an EP1 knockdown. Similar observations were made with M1 collecting duct and rabbit kidney proximal tubule cells. ONO-8711 even stimulates growth in the absence of exogenous PGE2, an effect that is prevented by ibuprofen (indicating a dependence upon endogenous PGE2). The involvement of Akt was indicated by the observation that 1) ONO-8711 and SC51089 increase Akt phosphorylation, and 2) MK2206, an Akt inhibitor, prevents the increased growth caused by ONO-8711. The involvement of the EGF receptor (EGFR) was indicated by 1) the increased phosphorylation of the EGFR caused by SC51089 and 2) the loss of the growth-stimulatory effect of ONO-8711 and SC51089 caused by the EGFR kinase inhibitor AG1478. The growth-stimulatory effect of ONO-8711 was lost following an EGFR knockdown, and transduction of MDCK cells with a dominant negative EGFR. These results support the hypothesis that 1) signaling via the EP1 receptor involves Akt as well as the EGFR, and 2), EP1 receptor pharmacology may be employed to prevent the aberrant growth associated with a number of renal diseases., (Copyright © 2014 the American Physiological Society.)
- Published
- 2014
- Full Text
- View/download PDF