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

Am J Physiol Renal Physiol. 2011 Dec;301(6):F1303-13. doi: 10.1152/ajprenal.00665.2010. Epub 2011 Aug 31.

Abstract

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(-/-), 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(-/-), 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(-/-) mice irrespective of gender. Hypothalamic AVP mRNA level increased and was unchanged between COX-2(-/-) and WT after WD. AVP peptide content was higher in COX-2(-/-) compared with WT. At baseline, plasma AVP concentration was elevated in conscious chronically catheterized COX-2(-/-) mice, but after WD plasma AVP was unchanged between COX-2(-/-) and WT mice (43 ± 11 vs. 70 ± 16 pg/ml). Renal V2 receptor abundance was downregulated in COX-2(-/-) mice. Medullary interstitial osmolality increased and did not differ between COX-2(-/-) 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(-/-) at baseline and further increased after WD. COX-2(-/-) 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(-/-) is likely caused by developmental glomerular injury and not dysregulation of AVP or collecting duct aquaporins.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aquaporin 2 / analysis
  • Aquaporin 3 / analysis
  • Arginine Vasopressin / blood
  • Arginine Vasopressin / metabolism
  • Creatinine / blood
  • Cyclooxygenase 2 / genetics
  • Cyclooxygenase 2 / metabolism*
  • Female
  • Hypothalamus / enzymology
  • Kidney / metabolism
  • Kidney Concentrating Ability*
  • Male
  • Membrane Transport Proteins / analysis
  • Mice
  • Mice, Inbred C57BL
  • Receptors, Vasopressin / analysis
  • Urea / blood
  • Water Deprivation / physiology
  • Water-Electrolyte Balance / physiology

Substances

  • Aqp2 protein, mouse
  • Aqp3 protein, mouse
  • Aquaporin 2
  • Membrane Transport Proteins
  • Receptors, Vasopressin
  • UT-A1 protein, mouse
  • Arginine Vasopressin
  • Aquaporin 3
  • Urea
  • Creatinine
  • Ptgs2 protein, mouse
  • Cyclooxygenase 2