Role of Microsomal Prostaglandin E Synthase 1 in the Kidney

Abstract

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.

MF63 [2-(6-Chloro-1H-phenanthro[9,10-d]imidazol-2-yl)-isophthalonitrile], a Selective Microsomal Prostaglandin E Synthase-1 Inhibitor, Relieves Pyresis and Pain in Preclinical Models of Inflammation

“…Besides thrombosis, an increase in blood pressure is another cardiovascular risk factor. Although mPGES-1 deletion further increases blood pressure in mice with extremely high salt load (saline plus 3.5% of dietary NaCl) (Jia et al, 2006), it does not have any impact on hypertension under standard high salt conditions (6 -8% dietary sodium) (Cheng et al, 2006;Francois et al, 2007) known to cause exaggerated hypertension in mice lacking COX-2 (Cheng et al, 2006).…”

Two Pathways for Cyclooxygenase-2 Protein Degradation in Vivo

“…It is not known why the levels of urinary PG metabolites are so much higher in the male than the female mice in C57BL/6J mice. This is clearly dependent on the genetic background of the mice because females have higher levels of PGE 2 urinary metabolites than the males in the DBA/1 mouse background (31).…”

Enhanced pressor response to acute Ang II infusion in mice lacking membrane-associated prostaglandin E2 synthase-1

“…This exaggerated hypertensive response may be due in part to the inability of the kidneys of mPGES-1 -/-mice to sufficiently excrete the sodium load. However, whether mPGES-1 is essential for high salt-induced hypertension is a matter of debate because of inconsistent findings [31,32] . Therefore, whether vascular mPGES-1 is involved in blood pressure regulation and contributes to salt-sensitive hypertension remains unclear [39] .…”