Prostaglandin E2 receptor EP1 (PGE2/EP1) deletion promotes glomerular podocyte and endothelial cell injury in hypertensive TTRhRen mice

Prostaglandin E2 receptor EP1 (PGE 2 /EP 1 ) promotes diabetic renal injury, and EP 1 receptor deletion improves hyperfiltration, albuminuria, and fibrosis. The role of EP 1 receptors in hypertensive kidney disease (HKD) remains controversial. We examined the contribution of EP 1 receptors to HKD. EP 1 null (EP 1 −/− ) mice were bred with hypertensive TTRhRen mice (Htn) to evaluate kidney function and injury at 24 weeks. EP 1 deletion had no effect on elevation of systolic blood pressure in Htn mice (HtnEP 1 −/− ) but resulted in pronounced albuminuria and reduced FITC-inulin clearance, compared with Htn or wild-type (WT) mice. Ultrastructural injury to podocytes and glomerular endothelium was prominent in HtnEP 1 −/− mice; including widened subendothelial space, subendothelial lucent zones and focal lifting of endothelium from basement membrane, with focal subendothelial cell debris. Cortex COX2 mRNA was increased by EP 1 deletion. Glomerular EP 3 mRNA was reduced by EP 1 deletion, and EP 4 by Htn and EP 1 deletion. In WT mice, PGE 2 increased chloride reabsorption via EP 1 in isolated perfused thick ascending limb (TAL), but PGE 2 or EP 1 deletion did not affect vasopressin-mediated chloride reabsorption. In WT and Htn mouse inner medullary collecting duct (IMCD), PGE 2 inhibited vasopressin-water transport, but not in EP 1 −/− or HtnEP 1 −/− mice. Overall, EP 1 mediated TAL and IMCD transport in response to PGE 2 is unaltered in Htn, and EP 1 is protective in HKD.