prostaglandin-d2 and Dehydration

Papillary cells adapt to their hyperosmotic environment by accumulating organic osmolytes and by enhanced synthesis of heat shock protein 70 (HSP70), which protect against high-solute concentrations. Because cyclooxygenase-2 (COX-2) is expressed abundantly in the renal papilla and is induced by dehydration, and because HSP70 expression is stimulated by specific prostaglandins, COX-2 inhibition may interfere with cellular osmoadaptation.. In vivo, rats received rofecoxib before water deprivation. Medullary expression of several tonicity-responsive genes was analyzed and apoptosis was monitored by transferase-mediated dUTP nick-end labeled (TUNEL) staining and determination of papillary caspase-3 activity. In vitro, inner medullary collecting duct 3 (IMCD3) cells were exposed to hypertonic medium containing a COX-2-specific inhibitor. Thereafter, expression of tonicity-responsive genes was analyzed and resistance to high-solute concentrations was examined. Further, the effect of Delta 12-PGJ2, a urinary prostaglandin, and of HSP70 overexpression on resistance against high urea concentration, was evaluated.. Rofecoxib treatment significantly increased urine osmolality due to higher urea concentrations, but reduced papillary HSP70 abundance by 50%. TUNEL staining showed numerous apoptotic cells in the papilla, associated with increased caspase-3 activity. These in vivo results were confirmed by experiments on cultured IMCD3 cells, in which COX-2 inhibition impaired the tonicity-induced up-regulation of HSP70 expression and rendered the cells susceptible to high urea concentrations. Furthermore, Delta 12-PGJ2 increased both HSP70 expression and resistance against high urea, which was causally linked to higher HSP70 levels.. These observations support the view that chronic COX-2 inhibition reduces medullary HSP70 expression, thus rendering papillary cells susceptible to damage by high urea concentrations, especially when accompanied by dehydration.

Topics: Animals; Antineoplastic Agents; Apoptosis; Cells, Cultured; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Dehydration; Gene Expression Regulation, Enzymologic; HSP70 Heat-Shock Proteins; Hypertonic Solutions; Isoenzymes; Kidney Concentrating Ability; Kidney Medulla; Lactones; Male; Osmolar Concentration; Prostaglandin D2; Prostaglandin-Endoperoxide Synthases; Rats; Rats, Wistar; Sulfones; Water Deprivation; Water-Electrolyte Balance

Brain-derived angiotensin II (ANG II) and prostaglandins have important roles in the regulation of body fluid and blood pressure homeostasis. In the present studies we investigated the central interactions between these two neurochemical products in regulating the hypothalamo-neurohypophysial system during dehydration. Intracerebroventricular (icv) administration of prostaglandin D(2) (PGD(2); 20 microg/5 microl) to conscious adult male Sprague-Dawley rats deprived of water for 24 h did not alter significantly the already elevated plasma levels of vasopressin or oxytocin. When PGD(2) was administered in combination with losartan, an antagonist of ANG II AT(1)-receptor subtype, however, concentrations of both hormones in plasma became further elevated. Icv administration of ANG II (50 ng/5 microl) increased further the enhanced plasma levels of vasopressin and oxytocin, as expected. Pretreatment with indomethacin (200 microg/5 microl; icv), an inhibitor of cyclo-oxygenase, significantly attenuated the ANG II-induced increase in oxytocin secretion only. Independent of the presence of ANG II, however, indomethacin decreased plasma levels of vasopressin, but not oxytocin. These results indicate that a prostaglandin is required for the stimulated release of vasopressin during dehydration and that the elevation of oxytocin secretion in response to ANG II depends largely on activation of cyclo-oxygenase and production of prostaglandins. The oxytocin response to exogenously administered PGD(2), however, can be negatively modulated by a mechanism dependent upon ANG II AT(1) receptors.

Topics: Angiotensin II; Animals; Antihypertensive Agents; Brain Chemistry; Central Nervous System; Cyclooxygenase Inhibitors; Dehydration; Indomethacin; Injections, Intraventricular; Losartan; Male; Oxytocin; Prostaglandin D2; Radioimmunoassay; Rats; Rats, Sprague-Dawley; Vasoconstrictor Agents; Vasopressins