Kidney Week

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

• Diabetic Kidney Disease: Basic - II
  November 08, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Diabetic Kidney Disease

• 601 Diabetic Kidney Disease: Basic

Authors

• Nasrallah, Rania, University of Ottawa, Ottawa, Ontario, Canada

Rania Nasrallah,

• Zimpelmann, Joe A., University of Ottawa, Ottawa, Ontario, Canada

Joe A. Zimpelmann,

• Burns, Kevin D., University of Ottawa, Ottawa, Ontario, Canada

Kevin D. Burns,

• Hébert, Richard L., University of Ottawa, Ottawa, Ontario, Canada

Richard L. Hébert,

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.