Renal effects induced by prolonged mPGES1 inhibition

Abstract

The importance of membrane-bound PGE synthase 1 (mPGES1) in the regulation of renal function has been examined in mPGES1-deficient mice or by evaluating changes in its expression. However, it is unknown whether prolonged mPGES1 inhibition induces significant changes of renal function when Na+ intake is normal or low. This study examined the renal effects elicited by a selective mPGES1 inhibitor (PF-458) during 7 days in conscious chronically instrumented dogs with normal Na+ intake (NSI) or low Na+ intake (LSI). Results obtained in both in vitro and in vivo studies have strongly suggested that PF-458 is a selective mPGES1 inhibitor. The administration of 2.4 mg·kg−1·day−1 PF-458 to dogs with LSI did not induce significant changes in renal blood flow (RBF) and glomerular filtration rate (GFR). A larger dose of PF-458 (9.6 mg·kg−1·day−1) reduced RBF (P < 0.05) but not GFR in dogs with LSI and did not induce changes of renal hemodynamic in dogs with NSI. Both doses of PF-458 elicited a decrease (P < 0.05) in PGE2 and an increase (P < 0.05) in 6-keto-PGF1α. The administration of PF-458 did not induce significant changes in renal excretory function, plasma renin activity, and plasma aldosterone and thromboxane B2 concentrations in dogs with LSI or NSI. The results obtained suggest that mPGES1 is involved in the regulation of RBF when Na+ intake is low and that the renal effects elicited by mPGES1 inhibition are modulated by a compensatory increment in PGI2. These results may have some therapeutical implications since it has been shown that prolonged mPGES1 inhibition has lower renal effects than those elicited by nonsteroidal anti-inflammatory drugs or selective cyclooxygenase-2 inhibitors.