PGE(2) EP(3) Receptor Downregulates COX-2 Expression in the Medullary Thick Ascending Limb Induced by Hypertonic Nacl

Authors

Shoujin Hao, Department of Pharmacology, New York Medical College, Valhalla, New York; and.
Alejandra Hernandez, Department of Physiology, Center for Aging and Regeneration, CARE Chile UC, Facultad de Ciencias Biologicas, Pontificia Universidad Catolica de Chile, Santiago, Chile.
Mariana Quiroz-Munoz, Department of Physiology, Center for Aging and Regeneration, CARE Chile UC, Facultad de Ciencias Biologicas, Pontificia Universidad Catolica de Chile, Santiago, Chile.
Carlos Cespedes, Department of Physiology, Center for Aging and Regeneration, CARE Chile UC, Facultad de Ciencias Biologicas, Pontificia Universidad Catolica de Chile, Santiago, Chile.
Carlos P. Vio, Department of Physiology, Center for Aging and Regeneration, CARE Chile UC, Facultad de Ciencias Biologicas, Pontificia Universidad Catolica de Chile, Santiago, Chile.
Nicholas R. Ferreri, Department of Pharmacology, New York Medical College, Valhalla, New York; and nick_ferreri@nymc.edu.

Author Type(s)

Faculty

DOI

10.1152/ajprenal.00204.2014

Journal Title

American Journal of Physiology. Renal Physiology

First Page

F736

Last Page

46

Document Type

Article

Publication Date

9-15-2014

Abstract

We tested the hypothesis that inhibition of EP3 receptors enhances cyclooxygenase (COX)-2 expression in the thick ascending limb (TAL) induced by hypertonic stimuli. COX-2 protein expression in the outer medulla increased approximately twofold in mice given free access to 1% NaCl in the drinking water for 3 days. The increase was associated with an approximate threefold elevation in COX-2 mRNA accumulation and an increase in PGE2 production by isolated medullary (m)TAL tubules from 77.3 ± 8.4 to 165.7 ± 10.8 pg/mg protein. Moreover, administration of NS-398 abolished the increase in PGE2 production induced by 1% NaCl. EP3 receptor mRNA levels also increased approximately twofold in the outer medulla of mice that ingested 1% NaCl. The selective EP3 receptor antagonist L-798106 increased COX-2 mRNA by twofold in mTAL tubules, and the elevation in COX-2 protein induced by 1% NaCl increased an additional 50% in mice given L-798106. COX-2 mRNA in primary mTAL cells increased twofold in response to media made hypertonic by the addition of NaCl (400 mosmol/kg H2O). L-798106 increased COX-2 mRNA twofold in isotonic media and fourfold in cells exposed to 400 mosmol/kg H2O. PGE2 production by mTAL cells increased from 79.3 ± 4.6 to 286.7 ± 6.3 pg/mg protein after challenge with 400 mosmol/kg H2O and was inhibited in cells transiently transfected with a lentivirus short hairpin RNA construct targeting exon 5 of COX-2 to silence COX-2. Collectively, the data suggest that local hypertonicity in the mTAL is associated with an increase in COX-2 expression concomitant with elevated EP3 receptor expression, which limits COX-2 activity in this segment of the nephron.

Recommended Citation

Hao, S., Hernandez, A., Quiroz-Munoz, M., Cespedes, C., Vio, C. P., & Ferreri, N. R. (2014). PGE(2) EP(3) Receptor Downregulates COX-2 Expression in the Medullary Thick Ascending Limb Induced by Hypertonic Nacl. American Journal of Physiology. Renal Physiology, 307 (6), F736-46. https://doi.org/10.1152/ajprenal.00204.2014