COX-2 disruption leads to increased central vasopressin stores and impaired urine concentrating ability in mice

Abstract

Nørregaard R, Madsen K, Hansen PB, Bie P, Thavalingam S, Frøkiaer J, Jensen BL. COX-2 disruption leads to increased central vasopressin stores and impaired urine concentrating ability in mice. Am J Physiol Renal Physiol 301: F1303-F1313, 2011. First published August 31, 2011 doi:10.1152/ajprenal.00665.2010.-It was hypothesized that cyclooxygenase-2 (COX-2) activity promotes urine concentrating ability through stimulation of vasopressin (AVP) release after water deprivation (WD). COX-2-deficient (COX-2 Ϫ/Ϫ , C57BL/6) and wild-type (WT) mice were water deprived for 24 h, and water balance, central AVP mRNA and peptide level, AVP plasma concentration, and AVP-regulated renal transport protein abundances were measured. In male COX-2 Ϫ/Ϫ , basal urine output and water intake were elevated while urine osmolality was decreased compared with WT. Water deprivation resulted in lower urine osmolality, higher plasma osmolality in COX-2 Ϫ/Ϫ mice irrespective of gender. Hypothalamic AVP mRNA level increased and was unchanged between COX-2 Ϫ/Ϫ and WT after WD. AVP peptide content was higher in COX-2 Ϫ/Ϫ compared with WT. At baseline, plasma AVP concentration was elevated in conscious chronically catheterized COX-2 Ϫ/Ϫ mice, but after WD plasma AVP was unchanged between COX-2 Ϫ/Ϫ and WT mice (43 Ϯ 11 vs. 70 Ϯ 16 pg/ml). Renal V2 receptor abundance was downregulated in COX-2 Ϫ/Ϫ mice. Medullary interstitial osmolality increased and did not differ between COX-2 Ϫ/Ϫ and WT after WD. Aquaporin-2 (AQP2; cortex-outer medulla), AQP3 (all regions), and UT-A1 (inner medulla) protein abundances were elevated in COX-2 Ϫ/Ϫ at baseline and further increased after WD. COX-2 Ϫ/Ϫ mice had elevated plasma urea and creatinine and accumulation of small subcapsular glomeruli. In conclusion, hypothalamic COX-2 activity is not necessary for enhanced AVP expression and secretion in response to water deprivation. Renal medullary COX-2 activity negatively regulates AQP2 and -3. The urine concentrating defect in COX-2 Ϫ/Ϫ is likely caused by developmental glomerular injury and not dysregulation of AVP or collecting duct aquaporins.aquaporins; PGE 2; water deprivation MICE DEFICIENT IN PGE 2 EP1 receptor signaling display a mild urine concentrating defect that is coupled to a lower vasopressin (AVP) mRNA level in the hypothalamus (30). However, the source of PGE 2 that potentially activates the EP1 receptor in the neurons of hypothalamic nuclei to promote AVP expression and secretion is not clear. Cyclooxygenase type 2 (COX-2) which is expressed in the hypothalamus (10), is a rapidly inducible enzyme isoform that is a likely candidate. Intracerebroventricular application of the nonselective COX inhibitor meclofenamate impairs hyperosmolality-induced AVP secretion (49). Hypothalamic supraoptic nucleus (SON) neurons are sensitive to experimental addition of prostanoids, particularly PGE 2 and PGF 2␣ (46), which promotes electric and secretory activity. It is not known whether hypothalamic COX-2 activity is regulated by physiological variations in plasma o...

Disruption of cyclooxygenase-2 prevents downregulation of cortical AQP2 and AQP3 in response to bilateral ureteral obstruction in the mouse

“…As observed recently (19), the present data confirmed that mice deficient in COX-2 display a compensatory upregulation of COX-1 and further showed that COX-1 was stimulated by BUO in the cortex. Thus the mice exhibit a larger sensitivity to BUO with more widespread upregulation of COX in kidney tissue compared with rats, for example, where cortical COX-1 and -2 did not change after BUO (16).…”

“…To address this question, COX-2 Ϫ/Ϫ and wild-type littermate mice on a C57BL/6 background were used for the experiments. The mild developmental renal injury in COX-2 Ϫ/Ϫ on a C57BL/6 background (19,29) with higher levels of AQP2 and AQP3 was not considered a drawback to test the present hypothesis regarding downregulation of AQPs in response to BUO. Wild-type and COX-2 Ϫ/Ϫ mice were subjected to BUO for 24 h, and renal tissue abundance and localization of COX-2, COX-1, and collecting duct AQP2 and -3 were determined.…”

“…Moreover, Olesen et al (21) demonstrated that EP 2 and EP 4 agonists increase both AQP2 phosphorylation and trafficking. We have demonstrated that COX-2 knockout mice (COX-2 Ϫ/Ϫ ) exhibit lower urine concentrating ability despite increased AQP2 and AQP3 abundances (19). Taken together, these contradictory observations on the regulatory impact of prostaglandins on renal aquaporin abundance/water transport prompt investigations into model systems where the contribution from distinct components of the very redundant system can be defined more precisely.…”

Deletion of cyclooxygenase-2 in the mouse increases arterial blood pressure with no impairment in renal NO production in response to chronic high salt intake

“…The cAMP excretion in COX-2 Ϫ/Ϫ mice on low salt was higher compared with COX-2 ϩ/ϩ on low salt. COX-2 Ϫ/Ϫ have elevated vasopressin expression already at baseline (25), which may account for the present lack of reactivity of cAMP to the stimulation of elevated NaCl.…”

“…However, the statistical significant interaction between genotype and salt intake with delta pressure as dependent variable suggests a complex interplay. COX-2 is expressed in the hypothalamus (25). COX-1 Ϫ/Ϫ mice on normal salt diet also display altered diurnal variations of blood pressure.…”