Dysfunction of Erythropoietin-Producing Interstitial Cells in the Kidneys of ICR-derived Glomerulonephritis (ICGN) Mice

Abstract

ABSTRACT. Anemia is a major secondary symptom in chronic renal disorder (CRD), but the precise cause of insufficient production of erythropoietin (EPO) remains unclear owing to the controversial localization of EPO-producing cells in the kidneys. The ICR-derived glomerulonephritis (ICGN) mouse, a new hereditary nephrotic mouse, is an appropriate model of anemia associated with CRD. By using an amplified in situ hybridization technique, we detected and counted the renal EPO-producing cells under both normoxic and hypoxic conditions. The expression levels of renal EPO mRNA were quantified and oxygen gradients were also assessed immunohistochemically. Amplified in situ hybridization clarified that EPO-producing cells were peritubular interstitial cells in the middle region of renal cortex in both ICR and ICGN mice. Hypoxia (7% O 2 ) induced low oxygen tension in proximal tubular epithelial cells of renal cortex, and increased the expression of EPO mRNA and the number of EPO-producing cells in both ICR and ICGN mice. However, hypoxia did not increase the serum EPO levels in ICGN mice. The ICGN mouse is a good model for anemia associated with CRD, and the suppression of EPO protein production in the renal EPO-producing cells is considered to be a potential cause of anemia associated with CRD. KEY WORDS: amplified in situ hybridization, anemia with chronic renal disorder (CRD), erythropoietin (EPO)-producing cell, hereditary nephrotic ICR-derived glomerulonephritis (ICGN) mouse, kidney.J. Vet. Med. Sci. 67(9): 891-899, 2005 Anemia associated with chronic renal disorder (CRD) is a major secondary symptom that appears in the early stages of renal disease. This anemia is initially mild; however, ultimately, severe anemia directly affects the quality of life (QOL) [25,37]. Anemia associated with CRD is normochromic and normocytic, and, based on case studies, insufficient serum levels of erythropoietin (EPO) are considered to be a major cause [6,25,37].EPO, a 30-34 kDa glycoprotein, is classified as part of the hematopoietic cytokine family [5,14,24], controls the erythropoiesis in the bone marrow, and regulates the proliferation, differentiation and survival of erythroid progenitor cells through EPO receptor (EPOR)-mediated signal transduction [5,12,14,24]. The kidney is a principal organ of EPO production, accounting for more than 90% under normal conditions, with extra-renal sources estimated to produce than 10% [3,26]. Due to its strong erythropoietic effect, recombinant human EPO (rhEPO) is generally used as a therapeutic agent for anemia associated with CRD [7,19]. However, the precise cause of the insufficient serum levels of EPO in anemia associated with CRD remains unclear, primarily owing to the lack of knowledge of the identity of the EPO-producing cells and how they are regulated in the kidneys.Studies on anemia associated with CRD have been mainly accomplished by using artificial models of acute renal failure, i.e. drug-induced, antibody-induced and/or nephrectomized animal models. Compared with these exper...

Erythropoietin-Producing Cells in the Liver of ICR-Derived Glomerulonephritis (ICGN) Mice

“…The EPO insufficiency in ICGN mice is considered to be the dysfunction of EPO production system in the kidneys. The comparison of the numbers of renal EPO-producing cells, the renal EPO mRNA levels and serum EPO levels between ICR and ICGN mice clarify that the suppression of EPO protein production by the mid-cortical interstitial cells are a potential cause of anemia associated with CRD in ICGN mice [18].…”

“…The EPO insufficiency in ICGN mice is considered to be the dysfunction of EPO production system in the kidneys. The comparison of the numbers of renal EPO-producing cells, the renal EPO mRNA levels and serum EPO levels between ICR and ICGN mice clarify that the suppression of EPO protein production by the mid-cortical interstitial cells are a potential cause of anemia associated with CRD in ICGN mice [18].The kidney is a principal organ of EPO production, accounting for more than 90% under normal conditions, with extra-renal sources estimated to produce less than 10% [1,11]. Although liver is verified to be the representative organ of extra-renal EPO production from neonatal stage [19], the EPO-producing cells in the liver is still controversial.…”

“…ICR-derived glomerulonephritis (ICGN) mouse established in the National Institute of Infectious Diseases (NIID; Tokyo, Japan) is a inbred mouse strain with a hereditary nephritic syndrome [9,10]. Homozygous ICGN mice develop the typical symptoms of nephrosis, i.e., proteinuria, hypoproteinemia, hyperlipidemia, severe anemia and systemic edema, and eventually die as a result of chronic renal disorder (CRD) [9,10,[13][14][15][16][17][18]. Various kinds of histological changes are observed in the kidneys of ICGN mice, including the excessive accumulation of extracellular matrix (ECM) components, the suppressive digestion of ECM, and the abnormality of cell kinetics [13][14][15].…”

Age-Related Pathophysiological Changes in Rats with Unilateral Renal Agenesis

“…The decreased renal production of erythropoietin (EPO) is a primary cause of anemia in humans [17] and experimental animals [35] with renal failure. As 40-50 week-old affected UUA rats had normal values of RBC and Hct, the presence of erythropenia in 10-30 week-old animals was unexpected.…”

Localization of Tissue Transglutaminase (tTG) in Kidney of ICR-Derived Glomerulonephritis (ICGN) Mice

“…However, intense signals for tTG, CTGF, and FN were ob- served in renal tubular cells and tubulointerstitium of the UUO group, suggesting both tTG and CTGF play concordant roles in the pathogenesis of renal tubulointerstitial fibrosis. In murine experimental crescentic glomerulonephritis (ecGN) induced by the administration of anti-GBM Ab to C57BL/6 mice, tTG and TGF-b1 were expressed mainly in the mesangial area [36]. Renal injury might be modulated by tTG and TGF-b1 in ecGN.…”