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P2Y2 receptor-mediated release of prostaglandin E₂ by IMCD is altered in hydrated and dehydrated rats: relevance to AVP-independent regulation of IMCD function

Departments of ¹Internal Medicine, ²Physiology, and ³Neurobiology and Anatomy, University of Utah Health Sciences Center, Salt Lake City; ⁴Nephrology Research, and ⁵Geriatric Research, Education, and Clinical Center, Veterans Affairs Salt Lake City Health Care System, Salt Lake City, Utah

Submitted 6 February 2005 ; accepted in final form 14 April 2005

Circulating vasopressin levels change in hydrated and dehydrated conditions and thus control osmotic water permeability (P_f) of the inner medullary collecting duct (IMCD). Prostaglandin E₂ (PGE₂) antagonizes vasopressin-induced P_f of IMCD. Previously, we showed that activation of P2Y2 receptor (P2Y2-R) in IMCD results in production and release of PGE₂, and P2Y2-R mRNA and protein are significantly elevated in inner medullas of hydrated rats compared with dehydrated rats. Therefore, we examined whether the altered expression of P2Y2-R in hydrated and dehydrated states is associated with corresponding changes in P2Y2-R-mediated PGE₂ release by the IMCD. Rats were hydrated by providing sucrose water as the sole drinking fluid or dehydrated by water deprivation for 2 days. This resulted in high output-low osmolality and low output-high osmolality urines in hydrated and dehydrated rats, respectively. In hydrated rats, there was a significant increase in tubular fluid PGE₂, measured indirectly by assessing the urinary PGE₂ metabolite. Stimulation of freshly isolated IMCD preparations in vitro with P2Y2-R agonist (ATPS) showed a marked increase in the release of PGE₂ in hydrated rats compared with normal rats. These responses were blunted in the IMCD prepared from dehydrated rats. The P2Y2-R-mediated PGE₂ release in the IMCD of hydrated rats was mediated largely by cyclooxygenase (COX)-1 as COX-1-specific inhibitor valeroyl salicylate completely blocked the release. The COX-2-specific inhibitor N5398 had only a modest and insignificant inhibitory effect. In conclusion, the increased sensitivity of purinergic-prostanoid interaction seen in the IMCD of hydrated rats may represent a novel vasopressin-independent regulatory mechanism of IMCD function.

cyclooxygenases; extracellular nucleotides; arginine vasopressin; purinergic; aquaporin; inner medullary collecting duct; prostaglandin E₂

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