Prostaglandin E2 EP3 receptor regulates the diuretic response to hypertonic stress (892.38)

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We recently showed that activation of prostaglandin E2 (PGE2) EP3 receptors during normal sodium intake is part of a negative feedback mechanism that attenuates cyclooxygenase‐2 (COX‐2) expression in the thick ascending limb (TAL). However, the functional effects of this mechanism have not been determined. Since PGE2 exhibits natriuretic and diuretic functions, we determined the consequences of EP3 receptor manipulation and its relationship to COX‐2 expression and activity in response to hypertonic saline stress. EP3 receptor expression in the outer medulla increased about 2‐fold in Sprague‐Dawley rats given free access to 1% NaCl in the drinking water for 7 days compared with tap water; p<0.05. Ingestion of 1% NaCl also increased COX‐2 mRNA accumulation and protein expression in freshly isolated mTAL tubules, an effect that was augmented when EP3 was blocked. Urine volume increased approximately 2.5‐fold during ingestion of 1% NaCl but was reduced by ~40% on days 1‐7 in rats pretreated with a EP3 receptor agonist (sulprostone: 20 μg·kg−1·day−1) for 3 days. The decrease in urine volume was associated with a decline in COX‐2‐dependent PGE2 synthesis. In contrast, the increase in urine volume induced by 1% NaCl intake was significantly augmented after pretreatment with a selective EP3 receptor antagonist (L‐798106: 100 μg·kg−1·day−1) and was associated with an increase in PGE2 synthesis. Collectively, the data suggest that the COX‐2/PGE2 signaling pathway involving EP3 underlies the diuretic response to increased NaCl intake. The mechanism that contributes to these effects is currently under investigation.Grant Funding Source: NIH HL34300, American Heart Association 12GRNT12060350, Fondecyt 1130741, PGB12‐2007 CARE UC‐SQM