Back to Search
Start Over
PGE2 receptor EP3 inhibits water reabsorption and contributes to polyuria and kidney injury in a streptozotocin-induced mouse model of diabetes.
- Source :
-
Diabetologia [Diabetologia] 2016 Jun; Vol. 59 (6), pp. 1318-28. Date of Electronic Publication: 2016 Mar 19. - Publication Year :
- 2016
-
Abstract
- Aims/hypothesis: 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.<br />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 EP3 to AVP-mediated fluid reabsorption.<br />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, 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.<br />Conclusions/interpretation: 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.
- Subjects :
- Animals
Aquaporins genetics
Aquaporins metabolism
Arginine Vasopressin metabolism
Disease Models, Animal
Male
Mice
Receptors, Prostaglandin E genetics
Receptors, Prostaglandin E, EP3 Subtype genetics
Kidney metabolism
Polyuria metabolism
Receptors, Prostaglandin E metabolism
Receptors, Prostaglandin E, EP3 Subtype metabolism
Streptozocin toxicity
Water metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1432-0428
- Volume :
- 59
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Diabetologia
- Publication Type :
- Academic Journal
- Accession number :
- 26995650
- Full Text :
- https://doi.org/10.1007/s00125-016-3916-5