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Abstract: FR-PO180

Empagliflozin Attenuates PGE2-Mediated Inhibition of Arginine Vasopressin-Stimulated Water Reabsorption in Type II Diabetic (db/db) Mouse Collecting Duct

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Nasrallah, Rania, University of Ottawa, Ottawa, Ontario, Canada
  • Zimpelmann, Joe A., University of Ottawa, Ottawa, Ontario, Canada
  • Burns, Kevin D., University of Ottawa, Ottawa, Ontario, Canada
  • Hébert, Richard L., University of Ottawa, Ottawa, Ontario, Canada
Background


Sodium-glucose cotransporter 2 inhibitors such as empagliflozin (EMPA) are promising therapeutics in diabetic kidney disease (DKD) since they lower blood glucose, induce diuresis, and reduce glomerular hyperfiltration and proteinuria. Prostaglandin E2 (PGE2), the main renal product of cyclooxygenase 2 (COX2), inhibits vasopressin (AVP) mediated water reabsorption in the collecting duct via its EP1 and EP3 receptors. We examined whether PGE2 inhibition of AVP-mediated water transport is affected by EMPA.

Methods


Four groups of male mice were studied: control (db/m), db/m+EMPA (10 mg/kg/day in chow for 6 weeks), diabetic (db/db), and db/db+EMPA. Collecting ducts were microdissected for quantitative PCR and water transport studies. Isolated perfused inner medullary collecting ducts were stimulated with 10-12M AVP followed by 10-7M PGE2.

Results

Collecting ducts from db/db mice expressed elevated mRNA for COX2, EP1 receptors, and vasopressin V2 receptors (n=4-6) compared to db/m mice, but levels were unaffected by EMPA. Urine PGE2 by ELISA was increased in db/db mice (n=5), but not altered by EMPA. AVP-stimulated water reabsorption was comparable in db/m and db/m+EMPA mice, and equally attenuated by up to 50% by PGE2. In db/db mice, the AVP response was reduced by 50%, and this reduction was unaffected by EMPA. However, a greater attenuation of AVP-mediated water transport in response to PGE2 was observed in db/db mice (62%), and this PGE2 attenuation was significantly reduced in response to EMPA, to 28% (n=3-4).

Conclusion

PGE2 levels and EP1 receptor expression are increased in type II diabetic mice, leading to attenuation of collecting duct AVP-stimulated water reabsorption. This attenuation is reduced in response to EMPA treatment, which may prevent excessive water losses.

Funding

  • Government Support - Non-U.S.