title: PGE2 receptor EP3 inhibits water reabsorption and contributes to polyuria and kidney injury in a streptozotocin-induced mouse model of diabetes.
abstract: The first clinical manifestation of diabetes is polyuria. The prostaglandin E2 (PGE2) receptor EP3 antagonises arginine vasopressin (AVP)-mediated water reabsorption and its expression is increased in the diabetic kidney. The purpose of this work was to study the contribution of EP3 to diabetic polyuria and renal injury.
  
  
  
  Male Ep 3 (-/-) (also known as Ptger3 (-/-)) mice were treated with streptozotocin (STZ) to generate a mouse model of diabetes and renal function was evaluated after 12 weeks. Isolated collecting ducts (CDs) were microperfused to study the contribution of EP3 to AVP-mediated fluid reabsorption.
  
  
  
  Ep 3 (-/-)-STZ mice exhibited attenuated polyuria and increased urine osmolality compared with wild-type STZ (WT-STZ) mice, suggesting enhanced water reabsorption. Compared with WT-STZ mice, Ep 3 (-/-)-STZ mice also had increased protein expression of aquaporin-1, aquaporin-2, and urea transporter A1, and reduced urinary AVP excretion, but increased medullary V2 receptors. In vitro microperfusion studies indicated that Ep 3 (-/-) and WT-STZ CDs responded to AVP stimulation similarly to those of wild-type mice, with a 60% increase in fluid reabsorption. In WT non-injected and WT-STZ mice, EP3 activation with sulprostone (PGE2 analogue) abrogated AVP-mediated water reabsorption; this effect was absent in mice lacking EP3. A major finding of this work is that Ep 3 (-/-)-STZ mice showed blunted renal cyclooxygenase-2 protein expression, reduced renal hypertrophy, reduced hyperfiltration and reduced albuminuria, as well as diminished tubular dilation and nuclear cysts.
  
  
  
  Taken together, the data suggest that EP3 contributes to diabetic polyuria by inhibiting expression of aquaporins and that it promotes renal injury during diabetes. EP3 may prove to be a promising target for more selective management of diabetic kidney disease.
authors.affiliation: Department of Cellular and Molecular Medicine, Kidney Research Centre, Faculty of Medicine, University of Ottawa, 451 Smyth Road, Room 2514, Ottawa, ON, Canada, K1H 8M5.
authors.forename: Ramzi
authors.initials: R
authors.lastname: Hassouneh
authors.affiliation: Department of Cellular and Molecular Medicine, Kidney Research Centre, Faculty of Medicine, University of Ottawa, 451 Smyth Road, Room 2514, Ottawa, ON, Canada, K1H 8M5.
authors.forename: Rania
authors.initials: R
authors.lastname: Nasrallah
authors.affiliation: Ottawa Hospital Research Institute, University of Ottawa, Ottawa, ON, Canada.
authors.forename: Joe
authors.initials: J
authors.lastname: Zimpelmann
authors.affiliation: Ottawa Hospital Research Institute, University of Ottawa, Ottawa, ON, Canada.
authors.forename: Alex
authors.initials: A
authors.lastname: Gutsol
authors.affiliation: Department of Cellular and Molecular Medicine, Kidney Research Centre, Faculty of Medicine, University of Ottawa, 451 Smyth Road, Room 2514, Ottawa, ON, Canada, K1H 8M5.
authors.forename: David
authors.initials: D
authors.lastname: Eckert
authors.affiliation: Department of Cellular and Molecular Medicine, Kidney Research Centre, Faculty of Medicine, University of Ottawa, 451 Smyth Road, Room 2514, Ottawa, ON, Canada, K1H 8M5.
authors.forename: Jamie
authors.initials: J
authors.lastname: Ghossein
authors.affiliation: Department of Cellular and Molecular Medicine, Kidney Research Centre, Faculty of Medicine, University of Ottawa, 451 Smyth Road, Room 2514, Ottawa, ON, Canada, K1H 8M5.|Ottawa Hospital Research Institute, University of Ottawa, Ottawa, ON, Canada.
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Burns
authors.affiliation: Department of Cellular and Molecular Medicine, Kidney Research Centre, Faculty of Medicine, University of Ottawa, 451 Smyth Road, Room 2514, Ottawa, ON, Canada, K1H 8M5. rlhebert@uottawa.ca.
authors.forename: Richard L
authors.initials: RL
authors.lastname: Hébert
mesh_terms: D000818:Animals; D020346:Aquaporins / Q000235:genetics / Q000378:metabolism; D001127:Arginine Vasopressin / Q000378:metabolism; D004195:Disease Models, Animal; D007668:Kidney / Q000378:metabolism*; D008297:Male; D051379:Mice; D011141:Polyuria / Q000378:metabolism*; D018078:Receptors, Prostaglandin E / Q000235:genetics / Q000378:metabolism*; D058308:Receptors, Prostaglandin E, EP3 Subtype / Q000235:genetics / Q000378:metabolism*; D013311:Streptozocin / Q000633:toxicity*; D014867:Water / Q000378:metabolism*
chemical_list: D020346:Aquaporins; C545648:Ptger3 protein, mouse; D018078:Receptors, Prostaglandin E; D058308:Receptors, Prostaglandin E, EP3 Subtype; D014867:Water; D001127:Arginine Vasopressin; D013311:Streptozocin
keywords: Aquaporins; Arginine vasopressin; Diabetic kidney disease; Isolated perfused cortical collecting duct; PGE2/EP3 receptors; Polyuria; Urine concentrating function