PGE(2) EP3 receptor downregulates COX-2 expression in the medullary thick ascending limb induced by hypertonic NaCl

Hao, SJ; Hernandez A.; Quiroz-Munoz, M; Cespedes, C; Vio, CP; Ferreri NR

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 PGE(2) 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 PGE(2) 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. PGE(2) 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.

Más información

Título según WOS: PGE(2) EP3 receptor downregulates COX-2 expression in the medullary thick ascending limb induced by hypertonic NaCl
Título según SCOPUS: PGE2 EP3 receptor downregulates COX-2 expression in the medullary thick ascending limb induced by hypertonic NACl
Título de la Revista: AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY
Volumen: 307
Número: 6
Editorial: AMER PHYSIOLOGICAL SOC
Fecha de publicación: 2014
Página de inicio: F736
Página final: F746
Idioma: English
DOI:

10.1152/ajprenal.00204.2014

Notas: ISI, SCOPUS