Serum erythropoietin levels and inhibitors of erythropoiesis in patients with chronic renal failure.

Fukushima, Y; Fukuda, Mitsuyuki; Yoshida, Kenichi; Yamaguchi, Akihiko; Nakamoto, Yasushi; Miura, Akira B.; Harada, Tadashi; Tsuchida, Seigi

doi:10.1620/tjem.150.1

Cited by 9 publications

(8 citation statements)

References 17 publications

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“…32 Indeed, the plasma EPO level is not low or even increased in the patients with mild or modest CRF. [33][34][35][36] In summary, mPGES-1 deletion improves renal function, urine concentrating capability, and albuminuria, accompanied by a marked attenuation of renal inflammation, in an Nx mouse model of CRF. Paradoxically, the null mice exhibit worsened anemia and suppressed EPO synthesis after renal mass reduction.…”

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confidence: 81%

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

Wang

Yang

2012

Hypertension

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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...

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confidence: 81%

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

Wang

Yang

2012

Hypertension

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“…Significant anaemia develops in general when the glomerular filtration rate falls below 40 to 20 mL/min and 1.73 m 2 body surface area (274, 276–278). Low Epo levels relative to the degree of anaemia were first shown by bioassay (276, 279–281) and later by radioimmunoassay (274, 275, 281–284). However, the observation that the plasma Epo level can increase on acute hypoxic stress in CKD patients indicates that the capacity to produce Epo is not necessarily abolished (274).…”

Section: Anaemia Of Renal Failurementioning

confidence: 99%

Erythropoietin after a century of research: younger than ever

Jelkmann¹

2007

European J of Haematology

342

291

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In the light of the enthusiasm regarding the use of recombinant human erythropoietin (Epo) and its analogues for treatment of the anaemias of chronic renal failure and malignancies it is worth remembering that today's success has been based on a century of laborious research. The concept of the humoral regulation of haematopoiesis was first formulated in 1906. The term ‘erythropoietin’ for the erythropoiesis‐stimulating hormone was introduced in 1948. Native human Epo was isolated in 1977 and its gene cloned in 1985. During the last 15 yr, major progress has been made in identifying the molecules controlling Epo gene expression, primarily the hypoxia‐inducible transcription factors (HIF) that are regulated by specific O2 and oxoglutarate requiring Fe2+‐containing dioxygenases. With respect to the action of Epo, its dimeric receptor (Epo‐R) has been characterised and shown to signal through protein kinases, anti‐apoptotic proteins and transcription factors. The demonstration of Epo‐R in non‐haematopoietic tissues indicates that Epo is a pleiotropic viability and growth factor. The neuroprotective and cardioprotective potentials of Epo are reviewed with a focus on clinical research. In addition, studies utilising the Epo derivatives with prolonged half‐life, peptidic and non‐peptidic Epo mimetics, orally active drugs stimulating endogenous Epo production and Epo gene transfer are reviewed.

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“…These results suggest that the decrease in oxygen transport resulting from erythropenia may be partially compensated by an increase in Hb contents in individual RBCs of large volume. Increased RBC volume and Hb content may be secondary to a reduced proliferation of erythrocytic progenitor cells due to relatively low level of EPO or possible inhibitors of erythropoiesis [8].…”

Section: Discussionmentioning

confidence: 99%

Age-Related Pathophysiological Changes in Rats with Unilateral Renal Agenesis

Amakasu

Suzuki

Katayama

et al. 2011

The Journal of Veterinary Medical Science

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ABSTRACT. Affected rats of the unilateral urogenital anomalies (UUA) strain show renal agenesis restricted to the left side. To determine whether unilateral renal agenesis is a risk factor for the progression of renal insufficiency, we studied age-related pathophysiological alterations in affected rats. Although body growth and food intake were normal, polydipsia and polyuria with low specific gravity were present at 10 weeks and deteriorated further with age. Blood hemoglobin concentrations were normal, though there was slight erythropenia with increased MCV and MCH. Although hypoalbuminemia, hypercholesterolemia, azotemia, and hypermagnesemia were manifested after age 20 weeks, neither hyperphosphatemia nor hypocalcemia was observed. Plasma Cre and UN concentrations gradually increased with age. Cre clearance was almost normal, whereas fractional UN excretion was consistently lower than normal. Proteinuria increased with age, and albumin was the major leakage protein. In addition to cortical lesions, dilated tubules, cast formation, and interstitial fibrosis were observed in the renal medulla of 50 week-old affected rats. Renal weight was increased 1.7-fold and glomerular number 1.2-fold compared with normal rats. These findings show that the remaining kidney in UUA rats is involved not only in compensatory reactions but experiences pathophysiological alterations associated with progressive renal insufficiency.KEY WORDS: compensatory reaction, polyuria, proteinuria, renal agenesis, renal lesion.J. Vet. Med. Sci. 73(6): 787-795, 2011 There is evidence that one functioning kidney instead of two (i.e., a 50% reduction in nephron mass) may not be sufficient to support normal renal function throughout life. For example, unilateral nephrectomy (UNx) in adult rats was found to reduce GFR [5,22], increase urinary volume [5], and decrease urinary maximum concentrating capacity [22]. Moreover, neonatal UNx resulted in systemic hypertension [34] and overt proteinuria [22], as well as a marked reduction in GFR. These observations suggest that the renal function of the remaining kidney deteriorates more severely when UNx is performed during the neonatal period than during adulthood. Unilateral renal agenesis (URA) is a common congenital anomaly of the kidney [24], occurring in 1:1,000 to 1:500 persons [33]. The incidences of proteinuria, hypertension, and renal insufficiency have been reported to be higher in human patients with URA and one normal kidney than in individuals with two normal kidneys [4]. The pathogenesis and course of these manifestations in the remaining kidney of patients with URA have not been well investigated, due, perhaps in part, to the absence of suitable animal models of human URA.We previously reported the foundation and establishment of a new rat strain, the UUA (Unilateral Urogenital Anomalies) strain, characterized by URA and malformations of reproductive organs restricted to the left side. The URA was inherited as polygenic trait with the incidence of 20-60% in the strain [2]. The remaining ...

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Serum erythropoietin levels and inhibitors of erythropoiesis in patients with chronic renal failure.

Cited by 9 publications

References 17 publications

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

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

Erythropoietin after a century of research: younger than ever

Age-Related Pathophysiological Changes in Rats with Unilateral Renal Agenesis

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