Abstract:We recently observed a strong increase of 5’-nucleotidase in renal fibroblasts of rats that were anemic due to an immunity against erythropoietin. In order to test if the change of 5’-nucleotidase was related with anemia, we studied the distribution of the enzyme in irradiated rats treated with phenylhydrazine. The hematocrit of these rats decrased to 15% within 4 days and erythropoietin levels were more than 200 times over controls. After 7 days a histochemical study showed that the enzymatic activity and the… Show more
“…Other proteins that label interstitial fibroblasts are the soluble guanylyl cyclase (sGC) (Theilig et al 2001 ) and the membrane-bound ecto-5′-nucleotidase (5′NT) (Dawson et al 1989 ; Le Hir et al 1989 ; Gandhi et al 1990 ). Both proteins recognize interstitial cells (Ito cells) in the liver as well (Schmid et al 1994 ; Theilig et al 2001 ) and are functionally related with regulation of hemodynamic parameters (Le Hir and Kaissling 1993 ).…”
Section: Identification Of Cortical Fibroblasts By Immunostainingsmentioning
confidence: 99%
“…Under chronic anemia (3 months) the plasma membrane surface of the 5′NT-positive fibroblasts increases by formation of additional cell processes (Fig. 11 ) (Le Hir et al 1989 , 1991 ). Fig.…”
Section: Role Of Fibroblasts In Regulation Of Regional Renal Hemodynamentioning
The renal interstitial compartment, situated between basement membranes of epithelia and vessels, contains two contiguous cellular networks. One network is formed by interstitial Wbroblasts, the second one by dendritic cells. Both are in intimate contact with each other. Fibroblasts are interconnected by junctions and connected to basement membranes of vessels and tubules by focal adhesions. Fibroblasts constitute the "skeleton" of the kidney. In the renal cortex, Wbroblasts produce erythropoietin and are distinguished from other interstitial cells by their prominent F-actin cytoskeleton, abundance of rough endoplasmic reticulum, and by ecto-5Ј-nucleotidase expression in their plasma membrane. The resident dendritic cells belong to the mononuclear phagocyte system and fulWl a sentinel function. They are characterized by their expression of MHC class II and CD11c. The central situation of Wbroblasts suggests that signals from tubules, vessels, and inXammatory cells converge in Wbroblasts and elicit an integrated response. Following tubular damage and inXammatory signals Wbroblasts proliferate, change to the myoWbroblast phenotype and increase their collagen production, potentially resulting in renal Wbrosis. The acquisition of a proWbrotic phenotype by Wbroblasts in renal diseases is generally considered a main causal event in the progression of chronic renal failure. However, it might also be seen as a repair process.
“…Other proteins that label interstitial fibroblasts are the soluble guanylyl cyclase (sGC) (Theilig et al 2001 ) and the membrane-bound ecto-5′-nucleotidase (5′NT) (Dawson et al 1989 ; Le Hir et al 1989 ; Gandhi et al 1990 ). Both proteins recognize interstitial cells (Ito cells) in the liver as well (Schmid et al 1994 ; Theilig et al 2001 ) and are functionally related with regulation of hemodynamic parameters (Le Hir and Kaissling 1993 ).…”
Section: Identification Of Cortical Fibroblasts By Immunostainingsmentioning
confidence: 99%
“…Under chronic anemia (3 months) the plasma membrane surface of the 5′NT-positive fibroblasts increases by formation of additional cell processes (Fig. 11 ) (Le Hir et al 1989 , 1991 ). Fig.…”
Section: Role Of Fibroblasts In Regulation Of Regional Renal Hemodynamentioning
The renal interstitial compartment, situated between basement membranes of epithelia and vessels, contains two contiguous cellular networks. One network is formed by interstitial Wbroblasts, the second one by dendritic cells. Both are in intimate contact with each other. Fibroblasts are interconnected by junctions and connected to basement membranes of vessels and tubules by focal adhesions. Fibroblasts constitute the "skeleton" of the kidney. In the renal cortex, Wbroblasts produce erythropoietin and are distinguished from other interstitial cells by their prominent F-actin cytoskeleton, abundance of rough endoplasmic reticulum, and by ecto-5Ј-nucleotidase expression in their plasma membrane. The resident dendritic cells belong to the mononuclear phagocyte system and fulWl a sentinel function. They are characterized by their expression of MHC class II and CD11c. The central situation of Wbroblasts suggests that signals from tubules, vessels, and inXammatory cells converge in Wbroblasts and elicit an integrated response. Following tubular damage and inXammatory signals Wbroblasts proliferate, change to the myoWbroblast phenotype and increase their collagen production, potentially resulting in renal Wbrosis. The acquisition of a proWbrotic phenotype by Wbroblasts in renal diseases is generally considered a main causal event in the progression of chronic renal failure. However, it might also be seen as a repair process.
Renal interstitial cells play an important role in renal function and renal diseases. We describe the morphology of renal interstitial cells in the healthy kidney. We distinguish within the renal interstitium (1) renal fibroblasts and (2) cells of the immune system. Fibroblasts are in the majority and constitute the scaffold of the kidney; they are interconnected by junctions, and are attached to tubules and vessels. Although the phenotype of fibroblasts shows some variation depending on their location in the kidney and on their functional stage, their recognition as fibroblasts is possible on account of structural features. Among the cell types of the second group, antigen-presenting dendritic cells are the most abundant in in the peritubular interstitial spaces of healthy kidneys. Their incidence is highest in the inner stripe of the outer medulla. They share some morphological features with fibroblasts but lack others--junctional complexes, morphologically defined connections with tubules and vessels, and the prominent layer of actin filaments under the plasma membrane--that are characteristic for fibroblasts. Dendritic cells in healthy kidneys are morphologically different from macrophages, which are characterized by abundant primary and secondary lysosomes. In healthy kidneys macrophages are restricted to the connective tissue of the renal capsule and the pelvic wall, and to the periarterial connective tissue. Lymphocytes are rare in healthy kidneys. The distinction of cell types by morphology is supported by differences of membrane proteins. Among all interstitial cells in the renal cortex, fibroblasts alone exhibit ecto-5'-nucleotidase. Dendritic cells constitutively have a high abundance of MHC class II protein. Both proteins are mutually exclusive. Rat macrophages display the membrane antigen ED 2 and lymphocytes exhibit specific surface antigens, depending on their type and functional stage, e.g., CD4 or CD8.
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...
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