title: Microsomal prostaglandin E synthase 1 deletion retards renal disease progression but exacerbates anemia in mice with renal mass reduction.
abstract: 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.
authors: Department of Internal Medicine, University of Utah and Veterans Affairs Medical Center, Salt Lake City, UT 84132, USA.
authors: Zhanjun
authors: Z
authors: Jia
authors: Haiping
authors: H
authors: Wang
authors: Tianxin
authors: T
authors: Yang
mesh_terms: D000740:Anemia / Q000378:metabolism* / Q000503:physiopathology; D000818:Animals; D001794:Blood Pressure / Q000502:physiology; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D017353:Gene Deletion; D019746:Intramolecular Oxidoreductases / Q000235:genetics* / Q000378:metabolism*; D007671:Kidney Concentrating Ability / Q000502:physiology; D007678:Kidney Glomerulus / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D008861:Microsomes / Q000201:enzymology*; D009392:Nephrectomy; D000071876:Prostaglandin-E Synthases; D051436:Renal Insufficiency, Chronic / Q000378:metabolism* / Q000473:pathology* / Q000503:physiopathology
chemical_list: D019746:Intramolecular Oxidoreductases; D000071876:Prostaglandin-E Synthases; C000605865:Ptges protein, mouse