PGE₂ receptor EP₃ inhibits water reabsorption and contributes to polyuria and kidney injury in a streptozotocin-induced mouse model of diabetes

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.