Microsomal Prostaglandin E Synthase 1 Deletion Retards Renal Disease Progression But Exacerbates Anemia in Mice With Renal Mass Reduction

Abstract

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 1␣ and renal interleukin 1␤ 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. (Hypertension. 2012;59:122-128.) • Online Data Supplement Key Words: prostaglandin E 2 Ⅲ chronic renal failure Ⅲ microsomal prostaglandin E synthase 1 Ⅲ cyclooxygenase 2 Ⅲ proteinuria C hronic kidney disease (CKD) is a progressive loss of renal function, eventuating in renal replacement therapydialysis or kidney transplantation. 1 The number of patients experiencing CKD is growing, as reflected by the increasing cases of renal replacement therapy. There are 26 million American adults with CKD, and millions of others are at increased risk. Unfortunately, there is no specific treatment unequivocally shown to slow the progression of CKD. Renal mass reduction in the rodents leads to systemic hypertension, chronic renal failure, proteinuria, and glomerulosclerosis, mimicking the major features of human CKD. This model in recent years contributes to the elucidation of the pathophysiology and the development of new therapies for this disease.Prostaglandin E 2 (PGE 2 ) is a major product of arachidonic acid metabolism that is sequentially catalyzed by cyclooxygenase (COX) and prostaglandin E synthase (PGES). PGE 2 is a pleiotropic hormone involved in multiple physiopathological processes, particularly in the inflammatory response. In recent years, the investigation of PGE 2 function has...

Characterization of an experimental model of progressive renal disease in rats

“…These models are based on the use of chemical substances [8][9][10] or surgical produres that considerably reduce the renal tissue mass [11][12][13][14][15][16] . The pharmacologic models consist on the use of substance with nephrotoxic potential, which produce injuries to the renal tissue through different molecular mechanisms [8][9][10] .…”

“…These models have the disadvantage that it is not always possible to establish the exact dose to produce a specific degree of renal insufficiency, in addition to the possible occurrence of side effects that may compromise the experimental model. On the other hand, the surgical procedures, characterized by the removal of portions of the renal tissue, have been widely used because they have a high survival rate and a low cost, do not have side effects and can be used to produce progressive levels of renal failure, as shown in this study [11][12][13][14][15][16] .…”

“…The discrepancy of these results could be explained by the use of differente species and/or lineages of animals and due to differences in surgical protocols of renal tissue removal [11][12][13][14] .…”

“…in creatinine clearance in rats and mice four weeks after 5/6 nephrectomy 12,13,21 . Under our experimental conditions, the creatinine clearance reduction in the group of severe uremia was of 87%.…”

“…This last model was originally described by Ormrod and Miller in 1980 11 , when the authors showed that surgical removal of a significant portion of the rat kidneys causes adaptive changes in remnant nephrons capable of leading to increase of glomerular filtration rate and urinary output. The subtotal nephrectomy model, which consists of unilateral nephrectomy associated to the removal of 5/6 of the remaining kidney, has been widely used as model of ESRD, defined as when the animal has 10% or less of its kidney function [11][12][13][14][15] . However, studies that followed the original description of Ormrod and Miller have not characterized the parameters of renal function and the histological changes resulting from CKD in this experimental of model of nephrectomy in different levels.…”