Inhibiting mPGES-2 impedes renal cyst growth in mice with polycystic kidney disease
Abstract
Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the development of multiple fluid-filled cysts in the kidneys, resulting in progressive decline and failure of renal function. Microsomal prostaglandin E synthase-2 (mPGES-2) is a unique bifunctional enzyme that catalyzes the conversion of prostaglandin H2 (PGH2) to prostaglandin E2 (PGE2) or to malondialdehyde (MDA) in conjunction with heme. PGE2 and MDA are key mediators that regulate cell growth and proliferation, respectively. In this study, we elucidated the functional role of mPGES-2 in ADPKD. By performing Western blot and immunohistochemical staining on the kidneys of patients with PKD and healthy controls, we showed that the expression levels of mPGES-2 markedly increased. We then crossed mPGES-2 knockout (Ptges2–/–) mice with Ksp-Cre; pkd1flox/+ mice to generate mPGES-2 knockout ADPKD (Ptges2–/–; PKD) mice. We showed that mPGES-2 depletion mitigated ADPKD progression in a mouse model. These findings were corroborated by in vitro experiments in embryonic kidney cells: the application of the mPGES-2 inhibitor SZ0232 (40, 80, and 160 μM) effectively suppressed cyst growth, suggesting a potential therapeutic option for ADPKD. Analysis of mPGES-2 metabolites revealed that mPGES-2 deficiency led to a reduction in PGE2 production, which has not been detected in other renal diseases, likely because of the diminished heme levels in ADPKD kidneys. Moreover, mPGES-2 was implicated in the regulation of the downstream signaling pathway involving β-catenin/STAT3-c-Myc via PGE2–EP4, which promoted abnormal proliferation of renal tubular epithelial cells and influenced cyst formation. Our findings suggest that targeting mPGES-2 is a viable therapeutic strategy for the management of ADPKD.