Quantitation of erythropoietin-producing cells in kidneys of mice by in situ hybridization: correlation with hematocrit, renal erythropoietin mRNA, and serum erythropoietin concentration.

Department of Medicine, Vanderbilt University, Nashville, TN 37232-2287.
Blood (Impact Factor: 9.78). 09/1989; 74(2):645-51.
Source: PubMed

ABSTRACT In situ hybridization was used to quantitate the cells that produce erythropoietin (EP) in the renal cortices of mice with varying severities of acute anemia and of mice recovering from severe, acute anemia. The number of EP-producing cells in the renal cortex increased in an exponential manner as hematocrit was decreased. Individual EP-producing cells had very similar densities of silver grains in autoradiograms regardless of whether they were from normal mice or from slightly, moderately or severely anemic animals. With increasingly severe anemia, total renal EP mRNA levels and serum EP concentrations showed increases that correlated with the number of renal EP-producing cells. These results indicate that as mice become more anemic, additional cells are recruited to produce EP rather than the cells already producing EP being stimulated to increase their individual production. In mildly and moderately anemic animals, small clusters of EP-producing cells were found in the inner cortex with large areas of cortex containing no EP-producing cells. In severely anemic mice, EP-producing cells were found throughout the inner cortex with only a very few found scattered in the outer cortex and outer medulla. The data indicate that only a subset of total renal interstitial cells produce EP. During recovery from severe, acute anemia, the numbers of EP-producing cells decreased exponentially as hematocrits rose and correlated with decreases in total renal EP mRNA and serum EP concentrations. These results suggest that following an acute blood loss and during the recovery from a blood loss, the capacity to deliver oxygen, as represented by hematocrit, is the major regulator of EP production.

  • [Show abstract] [Hide abstract]
    ABSTRACT: Erythropoiesis, the bone marrow production of erythrocytes by the proliferation and differentiation hematopoietic cells, replaces the daily loss of 1% of circulating erythrocytes that are senescent. This daily output increases dramatically with hemolysis or hemorrhage. When erythrocyte production rate of erythrocytes is less than the rate of loss, chronic anemia develops. Normal erythropoiesis and specific abnormalities of erythropoiesis that cause chronic anemia are considered during three periods of differentiation: a) multilineage and pre-erythropoietin-dependent hematopoietic progenitors, b) erythropoietin-dependent progenitor cells, and c) terminally differentiating erythroblasts. These erythropoietic abnormalities are discussed in terms of their pathophysiological effects on the bone marrow cells and the resultant changes that can be detected in the peripheral blood using a clinical laboratory test, the complete blood count.
    Blood reviews 03/2014; DOI:10.1016/j.blre.2014.01.002 · 7.19 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: CKD progresses with fibrosis and erythropoietin (Epo)-dependent anemia, leading to increased cardiovascular complications, but the mechanisms linking Epo-dependent anemia and fibrosis remain unclear. Here, we show that the cellular phenotype of renal Epo-producing cells (REPs) alternates between a physiologic Epo-producing state and a pathologic fibrogenic state in response to microenvironmental signals. In a novel mouse model, unilateral ureteral obstruction-induced inflammatory milieu activated NFκB and Smad signaling pathways in REPs, rapidly repressed the Epo-producing potential of REPs, and led to myofibroblast transformation of these cells. Moreover, we developed a unique Cre-based cell-fate tracing method that marked current and/or previous Epo-producing cells and revealed that the majority of myofibroblasts are derived from REPs. Genetic induction of NFκB activity selectively in REPs resulted in myofibroblastic transformation, indicating that NFκB signaling elicits a phenotypic switch. Reversing the unilateral ureteral obstruction-induced inflammatory microenvironment restored the Epo-producing potential and the physiologic phenotype of REPs. This phenotypic reversion was accelerated by anti-inflammatory therapy. These findings demonstrate that REPs possess cellular plasticity, and suggest that the phenotypic transition of REPs to myofibroblasts, modulated by inflammatory molecules, underlies the connection between anemia and renal fibrosis in CKD.
    Journal of the American Society of Nephrology 07/2013; DOI:10.1681/ASN.2013010030 · 9.47 Impact Factor
  • Revue Francaise de Transfusion et d& apos Hemobiologie 01/1991; 34(1). DOI:10.1016/S1140-4639(05)80088-7

Full-text (3 Sources)

Available from
May 28, 2014