Role of microsomal prostaglandin E synthase 1 in the kidney.
Prostaglandin E(2) (PGE(2)) is one of the most ubiquitous prostanoids in the kidney, where it may influence a wide range of physiologic functions. PGE(2) is generated through enzymatic metabolism of prostanoid endoperoxides by specific PGE synthases (PGES). Several putative PGES have been identified and cloned, including the membrane-associated, inducible microsomal PGES1 (mPGES1), which is expressed in the kidney. To evaluate the physiologic role of mPGES1 in the kidney, mice with targeted disruption of mPges1 gene were studied, with a focus on responses where PGE(2) has been implicated, including urinary concentration, regulation of blood pressure, and response to a loop diuretic. The absence of mPGES1 was associated with a 50% decrease in basal excretion of PGE(2) in urine (P < 0.001). In female but not male mPGES1-deficient mice, there was a reciprocal increase in basal excretion of other prostanoids. Nonetheless, urinary osmolalities were similar in mPges1(+/+) and mPges1(-/-) mice at baseline and after 12 h of water deprivation. Likewise, there were no differences in blood pressure between mPGES1-deficient and wild-type mice on control or high- or low-salt diets. The furosemide-induced increase in urinary PGE(2) excretion that was seen in wild-type mice was attenuated in mPGES1-deficient mice. However, furosemide-associated diuresis was reduced only in male, not female, mPGES1-deficient mice. Stimulation of renin by furosemide was not affected by mPGES1 deficiency. These data suggest that mPGES1 contributes to basal synthesis of PGE(2), but there are other pathways that lead to renal PGE(2) synthesis. Moreover, there are significant gender differences in physiologic contributions of mPGES1 to control kidney function.
Francois, H; Facemire, C; Kumar, A; Audoly, L; Koller, B; Coffman, T
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