PGE 2 receptor EP 3 inhibits water reabsorption and contributes to polyuria and kidney injury in a streptozotocin-induced mouse model of diabetes

Aims/hypothesis The first clinical manifestation of diabetes is polyuria. The prostaglandin E 2 (PGE 2 ) receptor EP 3 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 EP 3 to diabetic polyuria and renal injury. Methods 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 EP 3 to AVP-mediated fluid reabsorption. Results 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, EP 3 activation with sulprostone (PGE 2 analogue) abrogated AVP-mediated water reabsorption; this effect was absent in mice lacking EP 3 . 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. Conclusions/interpretation Taken together, the data suggest that EP 3 contributes to diabetic polyuria by inhibiting expression of aquaporins and that it promotes renal injury during diabetes. EP 3 may prove to be a promising target for more selective management of diabetic kidney disease.