Prostaglandin E2 receptor EP2 mediates the effect of cyclooxygenase 2 on secondary parathyroid hyperplasia in end-stage renal disease

Abstract

Background: Secondary hyperparathyroidism (SHPT) in patients with end-stage renal disease (ESRD) is characterized by hyperplasia of the parathyroid glands (PTGs), while the underlying mechanism is not completely understood. Previously we demonstrated a relationship between cyclooxygenase 2 (COX2) overexpression and parathyroid hyperplasia and here we investigate the role of COX2 downstream metabolic product prostaglandin E2 (PGE2) and its receptor EP2 in the pathogenesis of SHPT.

Methods: PTGs isolated from ESRD patients with advanced SHPT were used to test the expression of COX2-microsomal prostaglandin E synthase-1 (mPGES-1)-EP2 pathway. A diffuse proliferative section of the PTGs was used for tissue culture and treated with high phosphate (HPi) medium, COX2-PGE2-EP2 pathway inhibitors or agonists. EP2 short hairpin RNA (shRNA) lentivirus was locally applied to treat an SHPT rat model.

Results: In PTGs isolated from ESRD patients, enhanced immunoactivities of COX2, mPGES-1 and EP2 were observed. In primary cultured PTG tissues, HPi induced intact parathyroid hormone (iPTH) secretion, proliferating cell nuclear antigen (PCNA) expression and COX2 activity, while COX2 and EP2 inhibitors attenuated hyperparathyroidism promoted by HPi. Furthermore, PGE2 or EP2 agonist (butaprost) directly stimulated hyperparathyroidism, whereas EP2 receptor antagonist or cyclic adenosine monophosphate inhibitor attenuated the hyperparathyroidism promoted by PGE2 or butaprost. EP2 shRNA treatment significantly reduced excessive expressions of EP2 and PCNA in the PTGs of nephrectomy rats fed an HPi diet, diminished the size of PTGs and downregulated serum iPTH levels.

Conclusions: The COX2 downstream PGE2 and its receptor EP2 may play an important role in HPi-induced parathyroid hyperplasia and may serve as a potential therapeutic target for SHPT in ESRD.

Keywords: COX2–PGE2–EP2 receptor pathway; end-stage renal disease; high phosphate; parathyroid hyperplasia; secondary hyperparathyroidism.