A comparison of the effects of renal artery constriction and anemia on the production of erythropoietin

Pagel, Horst; Jelkmann, Wolfgang; Weiß, Ch.

doi:10.1007/bf00581229

Cited by 55 publications

(39 citation statements)

References 23 publications

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“…These data seem to be in contrast to the observation that selective reduction of oxygen supply to the kidneys by clamping of the renal arteries only causes a slight increase of the EPO formation rate, whereas lowering the systemic oxygen-transport capacity results in an exponential rise of serum EPO levels [20]. It should be remembered, however, that reduction of renal perfusion flow not only causes a reduction of renal oxygen delivery but also decreases the tubular sodium load and thereby locally alters renal oxygen consumption [4].…”

Section: Discussioncontrasting

confidence: 96%

“…Moreover, those experiments were partly performed in kidneys isolated from hypoxic animals, a fact that makes it difficult to distinguish whether EPO formation had been really induced or had merely been modulated during ex vivo perfusion [7]. A major argument against an essential "oxygen sensing" by the kidney is that a severe reduction of renal oxygen supply by selective reduction of renal perfusion only causes a slight increase of EPO formation while the same decrease of oxygen supply by a reduction of the systemic oxygen transport capacity leads to an exponentially increasing EPO production [20].…”

Section: Introductionmentioning

confidence: 99%

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Oxygen-dependent erythropoietin production by the isolated perfused rat kidney

et al. 1991

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Abstract. In this study we have investigated the role of oxygen delivery and of classic second messengers on erythropoietin production by the isolated perfused rat kidney. We found that the rat kidney was capable of de novo synthesis of erythropoietin. The erythropoietin production rate was inversely related to the oxygen pressure in the perfusate and increased from 0.17 to 1.85U erythropoietin h -1 g kidney -z when arterial PO2 was lowered from 500 mmHg to 30 mmHg. Addition of forskolin (10 gM) and 8-bromo-cGMP (100 gM) to the perfusate elicited significant effects on the renal vascular resistance, but had no significant effect on erythropoietin production. Hypoxia-induced erythropoietin formation, however, was blocked by calmidazolium (1 gM) and W-7 (10 lxM), two structurally different putative calmodulin antagonists. Calmidazolium and W-7 had no effect on other functional parameters of the isolated perfused rat kidney such as flow rate, glomerular filtration rate or sodium reabsorption. Our findings suggest that the oxygensensing mechanism that controls renal erythropoietin production is primarily located in the kidney itself. A cap cium/calmodulin-dependent cellular reaction could be involved in the signal transduction process.

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Section: Discussioncontrasting

confidence: 96%

Section: Introductionmentioning

confidence: 99%

Oxygen-dependent erythropoietin production by the isolated perfused rat kidney

et al. 1991

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“…The most well defined oxygen-dependent function of the kidney is the production of EPO (41), and we previously identified peritubular cortical fibroblasts as the cellular sites of hormone production (12,13). Three of the experimental conditions used in this investigation, i.e., anemia, CO, and CoCl 2 , strongly induce EPO mRNA in the kidney, whereas renal ischemia is only a weak stimulus for EPO production (42). Parallelism with the expression of HIF-2␣ in cortical peritubular cells, as observed in this study, Figure 9.…”

Section: Discussionmentioning

confidence: 81%

Expression of Hypoxia-Inducible Factor-1α and -2α in Hypoxic and Ischemic Rat Kidneys

Rosenberger¹,

Mandriota²,

Jürgensen³

et al. 2002

Journal of the American Society of Nephrology

531

387

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Abstract. Oxygen tensions in the kidney are heterogeneous, and their changes presumably play an important role in renal physiologic and pathophysiologic processes. A family of hypoxia-inducible transcription factors (HIF) have been identified as mediators of transcriptional responses to hypoxia, which include the regulation of erythropoietin, metabolic adaptation, vascular tone, and neoangiogenesis. In vitro, the oxygen-regulated subunits HIF-1␣ and -2␣ are expressed in inverse relationship to oxygen tensions in every cell line investigated to date. The characteristics and functional significance of the HIF response in vivo are largely unknown. Highamplification immunohistochemical analyses were used to study the expression of HIF-1␣ and -2␣ in kidneys of rats exposed to systemic hypoxia bleeding anemia, functional anemia (0.1% carbon monoxide), renal ischemia, or cobaltous chloride (which is known to mimic hypoxia). These treatments led to marked nuclear accumulation of HIF-1␣ and -2␣ in different renal cell populations. HIF-1␣ was mainly induced in tubular cells, including proximal segments with exposure to anemia/carbon monoxide, in distal segments with cobaltous chloride treatment, and in connecting tubules and collecting ducts with all stimuli. Staining for HIF-1␣ colocalized with inducible expression of the target genes heme oxygenase-1 and glucose transporter-1. HIF-2␣ was not expressed in tubular cells but was expressed in endothelial cells of a small subset of glomeruli and in peritubular endothelial cells and fibroblasts. The kidney demonstrates a marked potential for upregulation of HIF, but accumulation of HIF-1␣ and HIF-2␣ is selective with respect to cell type, kidney zone, and experimental conditions, with the expression patterns partly matching known oxygen profiles. The expression of HIF-2␣ in peritubular fibroblasts suggests a role in erythropoietin regulation.Sufficient oxygenation is a prerequisite for organ function. However, oxygen delivery to organs and tissue oxygen tensions within organs vary considerably. The kidney is characterized by an interesting paradox with respect to its oxygen supply. Although blood flow is high in relation to organ weight and the arteriovenous oxygen difference is small, shunt diffusion of oxygen and heterogeneous utilization lead to marked oxygen gradients (1,2). Oxygen supply to the renal medulla barely exceeds demand, and medullary oxygen tensions are approximately 10 mmHg (3-6). Cortical oxygen tensions are more heterogeneous but are also frequently less than the venous oxygen tensions (4,6 -8).The effects of oxygen on cellular functions of the kidney are poorly understood. High rates of oxygen consumption in the proximal tubule and thick ascending limb, together with limited oxygen supply, are thought to be responsible for the high sensitivity to ischemic injury (2,9,10). A physiologic function directly related to renal oxygen tensions is the production of erythropoietin (EPO) by peritubular cortical fibroblasts (11-13). Regulation of EPO occurs at the mRN...

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“…effects of cyclosporine, as well as renal haemodynamic alterations, tissue injury and release of inflammatory cytokines, have to be considered. Although in the intact kidney reduction in arterial renal blood flow is only a minor stimulus for EPO formation [22], abnormal perfusion in kidneys with minimal excretory function or regional vasoconstriction may be of more significance.…”

Section: Discussionmentioning

confidence: 99%

Role of excretory graft function for erythropoietin formation after renal transplantation

Eckardt

Frei

Kliem

et al. 1990

Eur J Clin Investigation

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Abstract.To examine the role of renal excretory function for erythropoietin (EPO) formation we have determined the kinetics of plasma immunoreactive EPO (irEPO) in patients with end-stage renal disease undergoing renal allotransplantation (RTX).In 13 patients with immediate excretory graft function (imGF) and stable haemoglobin (Hb) concentrations (median Hb 9.5 g dl-' and median irEPO 18 mU ml-' before RTX) irEPO increased significantly on day 4 after RTX to a median value of 29 mU m l~ ' and 2 days later reached a plateau of 34.4k3.3 mU ml-' (mean k SD of daily median values during days 6-20).In patients with imGF having acute blood loss and subsequently receiving transfusions, irEPO responded in an inverse fashion to changes in Hb concentrations.In 12 patients with delayed graft function (dGF) (median Hb 8.8 g dl-' and median irEPO 15 mU ml-' before RTX) irEPO levels during the period of excretory failure remained either unchanged or displayed marked variations with peak values greatly exceeding those of patients with imGF. These variations were not related to changes in Hb concentrations and irEPO levels did not change following alterations in Hb concentrations. Upon recovery of excretory function irEPO approached the values found in patients with imGF.The results suggest that an intact excretory renal function is not a prerequisite for the capability to produce EPO, but correlates with the oxygen-dependent regulation of EPO formation.

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A comparison of the effects of renal artery constriction and anemia on the production of erythropoietin

Cited by 55 publications

References 23 publications

Oxygen-dependent erythropoietin production by the isolated perfused rat kidney

Oxygen-dependent erythropoietin production by the isolated perfused rat kidney

Expression of Hypoxia-Inducible Factor-1α and -2α in Hypoxic and Ischemic Rat Kidneys

Role of excretory graft function for erythropoietin formation after renal transplantation

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