Structure-function correlations in erythropoietin formation and oxygen sensing in the kidney

Abstract

Summary. The kidney is the main site of erythropoietin (EPO) formation. Oxygen sensing in the kidney itself plays a major role in the control of EPO synthesis. By in situ hybridization it has been established that the EPO-producing cells are situated in the interstitium of the cortical labyrinth, but they have not been precisely identified. Morphological findings provide new insights into the location and mechanism of oxygen sensing in the kidney. In addition to causing an increase in the number of cells containing EPO messenger RNA, anemia provokes structural changes exclusively in the cortical labyrinth. Specifically, the fibroblasts become enlarged and show increased activity of 5'-nucleotidase, and the $1 segment of the proximal tubule shows similar alterations as in various models of hypoxia. Thus, structures that are situated in the close vicinity of the EPO-producing cells appear to be sensitive to decreased oxygen delivery.Key words: Erythropoietin -Kidney -AnemiaOxygen -Proximal tubule -Endothelium -Fibroblasts consisting of a polypeptide chain of 165 aminoacids and one O-linked and three N-linked carbohydrate chains [23,24]. It induces proliferation and differentiation of late erythroid precursors and thereby determines the rate of red cell formation [7]. EPO plasma concentrations are determined mainly by the rate of EPO production in the kidneys, which in turn is negatively controlled by oxygen delivery to the kidneys. Renal EPO formation is therefore an essential part of a negative feedback loop guaranteeing normal tissue oxygenation (Fig. 1). Thus, renal EPO production, and in consequence plasma EPO levels, are elevated during anemia (Fig. 2), arterial hypoxia, and increased oxygen affinity of hemoglobin, and they are reduced during polycythemia [3]. Circumstantial evidence, moreover, suggests that it is the renal interstitial oxygen pressure (PO2) that governs EPO production in the kidney. The mechanism by which renal EPO formation is adapted to oxygen delivery and local PO 2 is only poorly understood. In the following we will consider structural and functional relationships within the kidney that could be of importance for the oxygen-dependent regulation of EPO production.The kidney, aside from its roles in waste excretion and water and electrolyte homeostasis, carries responsibility for tissue oxygenation since it is, at least in adult life, the main site of erythropoietin (EPO) formation. EPO is a glycoprotein hormone * Preprint of a lecture to be read at the 22nd Congress of the "Gesellschaft ffir Nephrologie", Heidelberg, September 15-18, 1991 (Editor: Prof. Dr. E. Ritz, Heidelberg) Abbreviations: EPO=erythropoietin; MHC II=major histocompatibility class II antigen; PAS=Period-acid-Schiff reaction; Sl=first segment of proximal tubule; S2=second segment of proximal tubule Structural Aspects of EPO Formation TopographyAttempts to identify the site of erythropoietin formation in the kidney have been made using both immunohistochemistry and in situ hybridization. The first method failed to reve...

Co-localization of erythropoietin mRNA and ecto-5'-nucleotidase immunoreactivity in peritubular cells of rat renal cortex indicates that fibroblasts produce erythropoietin.

“…The group of bone marrowderived interstitial cells, although heteromorphic, is characterized by the presence of antigens of the major histocompatibility com-335 plex (MHC) I1 class (17). Indirect evidence suggests that this latter group of cells plays no role in EPO formation, because their depletion after whole-body irradiation does not affect renal EPO production (18). Resident interstitial cells, which have been termed fibrocytes or fibroblasts, are characterized by extended cytoplasmic processes.…”

Control of the Expression of Ecto-5’-Nucleotidase in Renal Fibroblasts in Cell Culture

“…Our hypothesis that the increase of ecto-5'-nucleotidase in renal fibroblasts in situ during anemia might be due to a substance produced locally, and more precisely to adenosine, orig inated from the observation that this effect of anemia was heterogeneously distributed within the renal parenchyme [17,28]. The results of the present study, showing an in crease of ecto-5'-nucleotidase upon addition of an adenosine analog to renal fibroblasts in tissue culture support our hypothesis.…”

“…Likewise, a particular sensitivity of the labyrinth to a decreased oxygen supply can be invoked to explain why the renal synthesis of erythropoietin is restricted to that region of the cortex [28], Both the expression of ecto-5'-nucleotidase and the synthesis of erythro poietin might be linked to oxygen supply through adenosine. It has been proposed that adenosine takes part via A?…”

“…In contrast with other seg ments of the nephron, the proximal tubule relies almost exclusively on aerobic metabo lism for energy production [26. 27], During anemia morphological alterations of the prox imal tubule suggestive of hypoxic damage oc cur in the cortical labyrinth while the proxi mal tubules appear unaltered in the medullary rays and in the outer medulla [28], The in crease of ecto-5'-nucleotidase in the fibro blasts of the cortical labyrinth might thus be a consequence of a local rise of adenosine con centration due to an energy deficit in proxi mal tubules.…”

Plasticity of renal endocrine function

“…They show that in the unstressed kidney EPO-expressing cells are located in the deep renal cortex (predominantly juxtamedullary region) and outer medulla (7,113,133). Notably, in the continuously hypoxic area of the inner medulla, no EPO-expressing cells are found (97). The origin of EPO-expressing cells is not fully clear.…”