Abstract 10366: Ep3 Receptor Contributes to Renal Ischemia and Inflammation During Development of Renal Pathologies and Hypertension in Pgis Deficient Mice

Introduction: Abnormalities in prostacyclin synthase (PGIS) cause hypertension and/or renal pathologies in humans and mice due to increased thromboxane A2 (TxA 2 ) produced by platelets and/or kidneys. However, the kidney, which is the key organ in blood pressure regulation, mainly produces prostaglandin E2 (PGE 2 ), which could evoke renal vasoconstriction via activating the E prostanoid receptor-3 (EP3) and the Tx prostanoid receptor (TP; the receptor of TxA 2 ). We hypothesized that increased PGE 2 in the kidney contributes to hypertension and renal pathologies in the above-mentioned disorders via activating the EP3 receptor. Methods: To unravel the effect of PGE 2 , we first generated mice deficient for both PGIS and EP3 ( Pgis -/- Ep3 -/- ) or both PGIS and cyclooxygenase-1 ( Pgis -/- Cox-1 -/- ). To further exclude the effect of TxA 2 produced by the platelet COX-1, chimeric mice with Cox-1 -/- in hematopoietic cells were created by bone marrow transplantations of Pgis -/- and Cox-1 -/- mice. Results: Significant increases in blood pressure and heart-to-body-weight ratio were observed in Pgis -/- mice compared with WT mice, which were secondary to renal inflammation and fibrosis. In contrast, Pgis -/- Ep3 -/- had less renal damage resulting in fewer cardiovascular disorders. Furthermore, compared with WT kidneys, Pgis -/- kidneys showed increased levels of PGE 2 without PGI 2 and TxA 2 production as measured with high performance liquid chromatography-mass spectrometry. EP3 deficiency drastically diminished the decrease in renal blood flow evoked by ACh in Pgis -/- perfused kidneys. Interestingly, Pgis -/- Cox-1 -/- mice, but not Pgis -/- mice engrafted with bone marrow cells from Cox-1 -/- mice, displayed a much smaller extent of renal fibrosis than Pgis -/- mice. Conclusions: Increased levels of PGE 2 in the kidney contribute to hypertension and renal pathologies in PGIS abnormalities via activating the EP3 receptor. Our findings suggest a novel mechanism for intrarenal PGE 2 regulation of blood pressure and renal hemodynamics.