| First Author | Nasrallah R | Year | 2015 |
| Journal | Lab Invest | Volume | 95 |
| Issue | 9 | Pages | 1044-55 |
| PubMed ID | 26121313 | Mgi Jnum | J:225715 |
| Mgi Id | MGI:5694269 | Doi | 10.1038/labinvest.2015.79 |
| Citation | Nasrallah R, et al. (2015) Prostaglandin E2 increases proximal tubule fluid reabsorption, and modulates cultured proximal tubule cell responses via EP1 and EP4 receptors. Lab Invest 95(9):1044-55 |
| abstractText | Renal prostaglandin (PG) E2 regulates salt and water transport, and affects disease processes via EP1-4 receptors, but its role in the proximal tubule (PT) is unknown. Our study investigates the effects of PGE2 on mouse PT fluid reabsorption, and its role in growth, sodium transporter expression, fibrosis, and oxidative stress in a mouse PT cell line (MCT). To determine which PGE2 EP receptors are expressed in MCT, qPCR for EP1-4 was performed on cells stimulated for 24 h with PGE2 or transforming growth factor beta (TGFbeta), a known mediator of PT injury in kidney disease. EP1 and EP4 were detected in MCT, but EP2 and EP3 are not expressed. EP1 was increased by PGE2 and TGFbeta, but EP4 was unchanged. To confirm the involvement of EP1 and EP4, sulprostone (SLP, EP1/3 agonist), ONO8711 (EP1 antagonist), and EP1 and EP4 siRNA were used. We first show that PGE2, SLP, and TGFbeta reduced H(3)-thymidine and H(3)-leucine incorporation. The effects on cell-cycle regulators were examined by western blot. PGE2 increased p27 via EP1 and EP4, but TGFbeta increased p21; PGE2-induced p27 was attenuated by TGFbeta. PGE2 and SLP reduced cyclinE, while TGFbeta increased cyclinD1, an effect attenuated by PGE2 administration. Na-K-ATPase alpha1 (NaK) was increased by PGE2 via EP1 and EP4. TGFbeta had no effect on NaK. Additionally, PGE2 and TGFbeta increased fibronectin levels, reaching 12-fold upon co-stimulation. EP1 siRNA abrogated PGE2-fibronectin. PGE2 also increased ROS generation, and ONO-8711 blocked PGE2-ROS. Finally, PGE2 significantly increased fluid reabsorption by 31 and 46% in isolated perfused mouse PT from C57BL/6 and FVB mice, respectively, and this was attenuated in FVB-EP1 null mice. Altogether PGE2 acting on EP1 and EP4 receptors may prove to be important mediators of PT injury, and salt and water transport. |
