Role of Microsomal Prostaglandin E Synthase 1 in the Kidney

Francois, H., Facemire, C., Kumar, A., Audoly, L., Koller, B., Coffman, T. — 2007-04-25

Prostaglandin E₂ (PGE₂) is one of the most ubiquitous prostanoids in the kidney, where it may influence a wide range of physiologic functions. PGE₂ 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 PGE₂ 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 PGE₂ 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 PGE₂ 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 PGE₂, but there are other pathways that lead to renal PGE₂ synthesis. Moreover, there are significant gender differences in physiologic contributions of mPGES1 to control kidney function.

Journal of the American Society of Nephrology Hemodynamics and Vascular Regulation

Role of Microsomal Prostaglandin E Synthase 1 in the Kidney