Microsomal
prostaglandin E synthase 1 (mPGES-1) is a
cytokine-inducible
enzyme responsible for generation of
prostaglandin E(2) (
PGE(2)) during the inflammatory response. In the present study, we investigated the role of mPGES-1 in the development of
chronic renal failure in mice with 5/6
nephrectomy (Nx). After 4 weeks of Nx, wild-type mice with renal mass reduction exhibited increased blood
urea nitrogen, plasma
creatinine and
phosphorus concentrations, and defective urine concentrating capability, all of which were significantly attenuated by mPGES-1 deletion. The Nx wild-type mice developed a 2.6-fold increase in urinary
albumin excretion, accompanied by glomerulosclerosis and reduction of
nephrin and wild-type 1 expression in the remnant kidney. In contrast, the Nx KO mice had normal
albuminuria with improvement of glomerular injury. Nx-induced increases in circulating and renal
tumor necrosis factor 1α and renal
interleukin 1β and
monocyte chemoattractant protein 1 expressions were all remarkably attenuated or abolished by mPGES-1 deletion. Paradoxically, the Nx knockout mice developed worsened
anemia, accompanied by impaired
erythropoietin synthesis. The coinduction of mPGES-1 and
cyclooxygenase 2 but not
cyclooxygenase 1 mRNA expressions, along with increased
PGE(2) synthesis, was demonstrated in the remnant kidney of wild-type mice. mPGES-1 deletion remarkably reduced renal
PGE(2) content and urinary
PGE(2) excretion after renal ablation but had a limited effect on the baseline
PGE(2) production. We conclude that mPGES-1 deletion ameliorates
chronic renal failure in the mouse model of renal mass reduction, and mPGES-1 deletion paradoxically exacerbates
anemia in this model likely via suppression of
erythropoietin synthesis.