Biomedical subjects

A Kurtz

Publications and source records attributed to A Kurtz.

At least 91 records · Page 5Linked to original sources

PubMed1997

The role of angiotensin II in the feedback control of renin gene expression.

This study aimed to characterize the influence of endogenous angiotensin II on renal renin gene expression during different states of a stimulated and of a suppressed renin system. To this end the renin system in male Sprague Dawley rats was stimulated by unilateral renal artery clipping (0.2 mm clip), by furosemide (60 mg/kg per diem) or isoproterenol (160 microg/kg per diem), and by ingestion of a low-salt diet (0.02%), or was suppressed by setting a contralateral renal artery clip (0.2-mm clip) or by ingestion of a high-salt diet (4%). During the last 2 days of these different treatment regimens, the animals were treated with the angiotensin II AT1 receptor antagonist losartan (40 mg/kg per diem) and renal renin mRNA levels were assayed. Renin gene expression was stimulated four- to fivefold by renal artery clipping and isoproterenol infusion, two- to three-fold by furosemide and a low-salt diet, and about four-fold by losartan. Additional treatment with losartan potentiated the stimulatory effects of a low-salt diet, of furosemide and of isoproterenol infusion on renin gene expression, whilst there was no significant additional effect of losartan on renin gene expression in clipped kidneys. Both contralateral renal artery clipping and a high-salt diet decreased renin mRNA levels to about 50% of the control value. In rts with a unilateral clip, additional losartan treatment caused renin mRNA to increase to about 350% of the control value in the contralateral kidney but to only 100% of the control value in animals on a high-salt diet. These findings suggest that the enhanced formation of angiotensin II during a low-salt intake, during tubular inhibition of salt reabsorption or during beta-adrenoreceptor activation plays a relevant negative feedback role in the activation of the renin gene. Moreover, in rats with one hypoperfused kidney, angiotensin II could be involved in the inhibition of renin gene expression in the contralateral kidney. In hypoperfused kidneys, however, and in animals on a high-salt diet, angiotensin II appears to play a only a minor feedback role in the regulation of the renin gene.

Angiotensin II↗

PubMed1997

In vivo carbon monoxide exposure and hypoxic hypoxia stimulate immediate early gene expression.

This study aimed to examine the influence of acute tissue hypoxygenation on the expression of immediate early genes in different rat tissues. To this end male Sprague-Dawley rats were exposed to 0.1% carbon monoxide for 0.5, 1 and 6 h or to 9% oxygen for 6 h and mRNA levels for c-jun, c-fos, c-myc and EGR-1 were assayed by RNase protection in hearts, kidneys, livers and lungs. We found that hypoxia increased c-jun mRNA levels between twofold (lung) and eightfold (liver) in all organs examined; c-fos mRNA increased between three-fold (lung) and 20-fold (heart); c-myc mRNA increased between twofold (lung) and sixfold (heart); and EGR-1 mRNA increased between twofold (lung) and sixfold (heart). Our findings suggest that acute tissue hypoxygenation is a general stimulus of the expression of immediate early genes in vivo. With regard to the sensitivity to hypoxia, organ differences appear to exist in that the lung is rather insensitive, whilst the heart is rather sensitive.

Animals↗

PubMed1997

Differential regulation of renal cyclooxygenase mRNA by dietary salt intake.

Experiments were done to investigate the influence of dietary salt intake on renal cyclooxygenase (COX) I and II mRNA levels. To this end rats were fed either a low NaCl diet (LS; 0.02% NaCl wt/wt) or a high NaCl diet (HS diet; 4% NaCl wt/wt) for 5, 10 and 20 days. After 10 days Na excretion differed 760-fold, plasma renin activity and renin mRNA were increased eight- and threefold in LS compared to HS animals. Total renal COX I mRNA decreased 50% following the LS diet and did not change after the HS diet. Conversely, COX II mRNA declined after HS intake and transiently increased after salt depletion. COX I and II mRNAs were unevenly distributed along the cortical-medullary axis with ratios of the cortex:outer medulla:papilla of 1:3:23 and 1:1:2, respectively. Cortical COX mRNAs were inversely regulated by salt intake with eightfold changes in COX II. Conversely, in medullary zones, COX I mRNA correlated directly with salt intake. We conclude that dietary salt intake influences renal cyclooxygenase mRNAs zone-specifically with opposite responses between cortex and medulla. Cortical COX II-mediated prostaglandin formation is probably important in low salt states whereas medullary COX I-produced prostaglandins seem to be more important for renal adaptation to a high salt intake.

Animals↗

PubMed1997

Effects of hypoxia on growth factor expression in the rat kidney in vivo.

There is accumulating evidence from in vitro studies suggesting that the genes of endothelin-1, PDGF, and VEGF are, like the erythropoietin gene, regulated by oxygen tension and by divalent cations. Hypoxia-induced stimulation of, such as endothelin-1, PDGF or VEGF might be involved in the pathogenesis of acute or chronic renal failure, and in renal "inflammatory" diseases (glomerulonephritis, vasculitis, allograft rejection). Hypoxia (8% O2) for six hours caused a 55-fold/1.6-fold increase of renal erythropoietin/endothelin-1 gene expression, whereas endothelin-3, PDGF-A, PDGF-B, and VEGF gene expression was unchanged. Carbon monoxide (0.1%) treatment for six hours stimulated renal erythropoietin gene expression 140-fold; however, endothelin-1, endothelin-3, PDGF-A, PDGF-B, and VEGF gene expression was not affected. Finally, cobalt treatment (60 mg/kg CoCl2) increased only renal erythropoietin/PDGF-B gene expression 5-fold/1.65-fold. These findings suggest that hypoxia is a rather weak stimulus for renal endothelin-1 gene expression, and that renal PDGF and VEGF gene expression in vivo is not sensitive to tissue hypoxia, in contrast to cell culture experiments. The in vivo regulation of endothelin-1, PDGF, and VEGF differs substantially from that of erythropoietin, suggesting that the basic gene regulatory mechanisms may not be the same.

Animals↗

PubMed1997

Induction of VEGF and VEGF receptor gene expression by hypoxia: divergent regulation in vivo and in vitro.

This study examined the expression of EPO, VEGF and VEGF receptor gene under conditions of reduced oxygen supply in primary cultures of rat hepatocytes, and compared it with the expression of these genes in hypoxic rat livers in vivo. To this end we exposed male Sprague-Dawley rats to hypoxia (10% and 8% O2), carbon monoxide (0.1% CO) or injected cobalt chloride (60 mg/kg CoCl2) subcutaneously. For the in vitro experiments we used primary cultures of rat hepatocytes which were kept at high (20% O2) and low (1% O2) oxygen tensions for three hours. The EPO mRNA was up-regulated by hypoxia in vitro and in vivo about 10-fold. The VEGF mRNA was up-regulated fivefold in the hepatocytes only, whereas the in vivo mRNA levels remained unchanged. The mRNA levels of flt-1 were up-regulated threefold by 8% O2 in livers, dependent on the strength of hypoxia (10% caused no changes in flt-1 gene expression) and on the kind of hypoxic stimulus (8% O2 was as effective as 0.1% CO and more effective than cobalt). The mRNA levels of flk-1/KDR and flt-4 remained unchanged in the liver. In vitro there were no changes in the mRNA levels of flt-1, flt-4 and flk-1/KDR. Consequently, the in vivo regulation of VEGF, which might be modulated by induction of flt-1 receptor gene expression, differs from the in vitro cell culture situation and might be different from the EPO regulation in vivo.

Animals↗

PubMed1997

Oxygen-dependent regulation of erythropoietin gene expression in rat hepatocytes.

The essential role of the glycoprotein hormone erythropoietin (Epo) in the control of red blood cell production is well established. Synthesis of Epo is induced in response to low oxygen (hypoxia). In response to stimulation, increases in serum Epo levels are paralleled by changes in the abundance of Epo mRNA. These changes indicate that the level of Epo mRNA is the major determinant of hormone production rate [1-3]. Studies of the organ distribution of Epo mRNA [4, 5] have confirmed the results of organ ablation studies, which demonstrated that in adults the kidney is the major organ responsible for the Epo production, but the liver is capable of Epo production as well [6, 7]. More sensitive detection methods of Epo mRNA have demonstrated small quantities in testis, brain, lung, and spleen of rodents [3, 8].

Animals↗

PubMed1997

Role of sympathetic nerves for the stimulation of the renin system by angiotensin II receptor blockade.

OBJECTIVE: To assess the relevance of sympathetic nerves for the stimulation of renin secretion and renin gene expression during effective angiotensin II type 1 receptor blockade in vivo. METHODS: Male Sprague-Dawley rats were treated with the angiotensin II type 1-receptor blocker losartan (40 mg/kg) for 3 days. To examine the role of renal sympathetic nerves in the stimulation of the renin system by losartan, left kidneys were denervated 4 days prior to the treatment with losartan. Also, to examine the role of circulating catecholamines in the stimulation of the renin system by losartan, the animals were administered a combination treatment of losartan with the beta1-adrenoreceptor blocker metoprolol (50 mg/kg per day) for 3 days. RESULTS: Losartan treatment increased plasma renin activity about sevenfold and renal renin messenger RNA (mRNA) levels about fivefold and decreased systolic blood pressure from 118 to 95 mmHg. Administration of losartan elevated renin mRNA both in the innervated and in the denervated kidneys to the same level as it did in kidneys of normal animals. Losartan treatment increased plasma renin activity and renal renin mRNA levels in the beta1-blocker-treated rats to the same extent as it did in animals administered losartan only. CONCLUSION: These findings suggest that, under sub-chronic treatment with hypotensive doses of angiotensin II receptor blockers, sympathetic outflow plays no important mediator role in the characteristic stimulation of renin secretion and renin gene expression, suggesting that it is mainly a direct disinhibition of angiotensin II's action on the level of juxtaglomerular cells that accounts for the effect.

Adrenergic beta-Antagonists↗

PubMed1997

Beta-adrenergic stimulation of renin expression in vivo.

OBJECTIVE: To characterize the effect of beta-adrenergic activation on renal production of renin in the intact organism. DESIGN AND METHODS: Renal expression of renin [renin messenger RNA (mRNA)], plasma renin activity (PRA), inactive renin level, intrarenal renin distribution (immunohistochemistry), and the time course of activation of renin as well as hemodynamic parameters were determined during the subcutaneous infusion of isoproterenol (ISO) into rats. To examine whether beta-adrenergic activation of the renin system is modulated by the rate of salt intake rats were fed diets with normal, low and high salt contents. RESULTS: Systolic blood pressure was not altered. PRA was elevated as much as fourfold after 40 h of ISO infusion. Although renal renin mRNA levels were elevated dose-dependently up to 4.2-fold, no significant recruitment of renin-containing cells could be detected. The time course of PRA revealed a marked transient rise of PRA during 6 h of ISO infusion with a subsequent decline. Inactive renin level was elevated during 3 to 18 h of ISO infusion. In contrast, renin mRNA level increased steadily with a lag phase of 3 h. Infusion of ISO increased PRA and renin mRNA level under a high-salt diet, but had no additional effect either on PRA or on renin mRNA level under low-salt diet. CONCLUSION: Activation of beta-adrenergic receptors is a powerful stimulus of renin secretion and renin gene expression in juxtaglomerular cells in vivo, albeit the kinetics of upregulation of renin secretion and renin expression are markedly different. Therefore, the sympathetic tone might be a major factor determining the activity of the renin system in vivo. The ability of adrenergic agonists to stimulate the renin system appears to be modulated by the steady-state level of salt intake.

Adrenergic beta-Antagonists↗

PubMed1997

Membrane and secretory properties of renal juxtaglomerular granular cells.

1. The control of renin secretion from renal juxtaglomerular granular cells on the cellular level is not yet completely understood. 2. There is evidence that calcium- and cyclic nucleotide-related pathways exert an opposite control of renin secretion. 3. There is accumulating evidence that the electrical properties of juxtaglomerular cells are important for the regulation of renin secretion.

Animals↗

PubMed1997

Acute hypoxia stimulates renin secretion and renin gene expression in vivo but not in vitro.

This study aimed at examining the influence of acute hypoxia on renin secretion and renin gene expression in the kidney. To this end, male Sprague-Dawley rats were exposed to severe hypoxic stress (8% O2) or to carbon monoxide (0.1% CO) for 6 h, and plasma renin activity (PRA) and renal renin mRNA levels were determined. PRA values increased from 3 to 13 and 10 ng angiotensin I x h(-1) x ml(-1), and renin mRNA levels increased by 120 and 100% during hypoxia and CO, respectively. Lowering the PO2 from 150 to 20 or 7 mmHg in the gas atmosphere of primary cultures of renal juxtaglomerular cells had no influence on renin secretion and renin gene expression after 6 and 20 h. Our findings thus suggest that both arterial and venous hypoxia can be powerful stimulators of renin secretion and renin gene expression in vivo. Because renal denervation did not prevent stimulation of the renin system by hypoxia, the effect could be indirectly mediated via the baroreceptor-macula densa mechanism. Another potential mediator of the effect could be circulating catecholamines, since we found that plasma norepinephrine increased from 0.7 to 1.5 and 2.4 ng/ml and plasma epinephrine increased from 0.3 to 1.4 and 2.7 ng/ml during hypoxia and CO inhalation, respectively.

Analysis of Variance↗

PubMed1997

Acute hypoxia upregulates NOS gene expression in rats.

This study aimed to investigate the influence of acute tissue hypoxygenation on the expression of NO synthase (NOS) genes in vivo. To this end, male Sprague-Dawley rats were exposed either to 9% oxygen or to 0.1% carbon monoxide for 6 h, and mRNA levels of NOS-I, -II, and -III in kidneys, livers, lungs, and left and right heart ventricles were assayed by ribonuclease protection. For comparison, mRNA levels of erythropoietin were also measured in these tissues. NOS-III mRNA was highly abundant in all organs investigated. NOS-II mRNA was detected in lungs and hearts but not in kidneys and livers. NOS-I mRNA was found in kidneys, lungs, and hearts but not in livers. NOS-III mRNA levels were upregulated by hypoxia in all tissues examined, with the least effect (1.2-fold) in the left ventricle and the greatest effect (2.6-fold) in the lung. NOS-II mRNA was substantially downregulated in the ventricles by both treatments but not changed in the lung. NOS-I mRNA was upregulated by carbon monoxide in kidneys and lungs and by 9% oxygen in the lung. These findings suggest that NOS-III and possibly also NOS-I gene expression behave like oxygen-regulated genes, whereas the general effect of tissue hypoxygenation on NOS-II gene expression is less clear. Because NOS-III is primarily expressed in endothelial cells, a general upregulation of NOS in these cells may be of relevance for the regulation and maintenance of blood flow through hypoxic tissues.

Actins↗

PubMed1997

Dietary salt intake modulates angiotensin II type 1 receptor gene expression.

This study aimed to characterize the influence of dietary salt intake on the gene expression of angiotensin II type 1 (AT1) receptor subtypes in different organs. Male Sprague-Dawley rats were fed low salt (0.2 mg/g), normal salt (6 mg/g), or high salt (40 mg/g) diets for 5, 10, and 20 days. mRNA levels for the two AT1 receptor subtypes were determined in adrenal gland, kidney, liver, and lung. In all of the organs examined, with the exception of the adrenal glands, low salt diet led to a transient decrease in the abundance of AT1A receptor mRNA but not of AT1B mRNA, which reached their nadirs between days 5 and 10 of feeding. In the adrenal gland, in which the AT1B receptor is predominant, low salt diet led to a transient increase in the expression of this receptor gene, with a maximum around day 10 of feeding. High salt diet exerted no significant influence on AT1 receptor gene expression in these organs. These findings indicate that the rate of salt intake, in particular, a reduction of salt intake, significantly influences AT1 receptor gene expression in an organ-, time-, and subtype-dependent fashion. It appears that AT1 receptor subtypes are differentially influenced by low salt intake, in that AT1B receptor gene expression increases and AT1A receptor gene expression decreases in this situation. This differential response of AT1 receptor gene expression may be relevant for the organism to be able to adapt to a reduction in oral salt intake.

Adrenal Glands↗

PubMed1997

Adrenomedullin stimulates renin release and renin mRNA in mouse juxtaglomerular granular cells.

The recently discovered peptide adrenomedullin (AM) alters blood pressure through effects on the resistance vessels. Moreover, AM modifies the secretion of corticotropin and aldosterone and could thereby indirectly influence blood pressure through the renin-angiotensin-aldosterone system. Although plasma AM and renin concentration have been found to directly correlate, a causal linkage between AM and renin has not been shown. The present study tested the influence of AM on renin secretion and renin gene expression by renal juxtaglomerular granular cells. Prominent expression and release of AM by vascular structures has been reported; therefore, we investigated the local expression of AM in juxtaglomerular structures. Renin release from isolated perfused rat kidneys was dose-dependently increased by AM (1 to 30 nmol/L), whereas renal perfusate flow rate increased up to 17% at a constant perfusion pressure of 100 mm Hg. In primary cultures of mouse granular cells, AM augmented renin release, renin mRNA accumulation, and cAMP production in a dose- and time-dependent manner (threshold values in the range 10 pmol/L to 1 nmol/L). By reverse transcription-polymerase chain reaction, significant expression of the AM gene was detected in microdissected rat glomeruli with afferent arterioles and in primary cultures of mesangial and granular cells. We conclude that AM is expressed in juxtaglomerular structures and that it has a direct stimulatory effect on renin secretion and renin mRNA abundance by receptors on juxtaglomerular cells, possibly through increases in cAMP. AM could act as an autocrine/paracrine stimulatory factor in the control of renin secretion and renin gene expression.

Adrenomedullin↗

PubMed1996

Human trophoblast and choriocarcinoma expression of the growth factor pleiotrophin attributable to germ-line insertion of an endogenous retrovirus.

Retroviral elements are found in abundance throughout the human genome but only rarely have alterations of endogenous genes by retroviral insertions been described. Herein we report that a human endogenous retrovirus (HERV) type C is inserted in the human growth factor gene pleiotrophin (PTN) between the 5' untranslated and the coding region. This insert in the human genome expands the region relative to the murine gene. Studies with promoter-reporter constructs show that the HERV insert in the human PTN gene generates an additional promoter with trophoblast-specific activity. Due to this promoter function, fusion transcripts between HERV and the open reading frame of PTN (HERV-PTN) were detected in all normal human trophoblast cell cultures as early as 9 weeks after gestation (n = 7) and in all term placenta tissues (n = 5) but not in other normal adult tissues. Furthermore, only trophoblast-derived choriocarcinoma cell lines expressed HERV-PTN mRNA whereas tumor cell lines derived from the embryoblast (teratocarcinoma) or from other lineages failed to do so. We investigated the significance of HERV-PTN mRNA in a choriocarcinoma model by targeting this transcript with ribozymes and found that the depletion of HERV-PTN mRNA prevents human choriocarcinoma growth, invasion, and angiogenesis in mice. This suggests that the tissue-specific expression of PTN due to the HERV insertion in the human genome supports the highly aggressive growth of human choriocarcinoma and possibly of the human trophoblast.

Amino Acid Sequence↗

PubMed1996

Expression of type II cGMP-dependent protein kinase in rat kidney is regulated by dehydration and correlated with renin gene expression.

cGMP-based regulatory systems are vital for counteracting the renin-angiotensin system (RAS) which promotes volume expansion and high blood pressure. Natriuretic peptides and nitric oxide acting through their second messenger cGMP normally increase natriuresis and diuresis, and regulate renin release; however, the severe pathological state of cardiac heart failure is characterized by elevated levels of atrial natriuretic peptide that are no longer able to effectively oppose exaggerated RAS effects. There is presently limited information on the intracellular effectors of cGMP actions in the kidney. Recently we reported the cloning of the cDNA for type II cGMP-dependent protein kinase (cGK II), which is highly enriched in intestinal mucosa but was also detected for the first time in kidney. In the present study, cGK II was localized to juxtaglomerular (JG) cells, the ascending thin limb (ATL), and to a lesser extent the brush border of proximal tubules. An activator of renin gene expression, the angiotensin II type I receptor inhibitor, losartan, increased cGK II mRNA and protein three to fourfold in JG cells. In other experiments, water deprivation increased cGK II mRNA and protein three to fourfold in the inner medulla where both cGK II, and a kidney specific CI- channel shown by others to be regulated by dehydration, are localized in the ATL. Whereas additional data suggest that cGK I may primarily mediate cGMP-related changes in renal hemodynamics, cGK II may regulate renin release and ATL ion transport.

Animals↗

PubMed1996

Hypoxia signalling in the control of erythropoietin gene expression in rat hepatocytes.

This study aimed to investigate the sequence of events involved in the stimulation of erythropoietin (EPO) gene expression by hypoxia in hepatocytes. To this end, primary cultures of rat hepatocytes were kept at either high (40% O2) or low (3% O2) oxygen tensions for 2.5 h. Hypoxia increased EPO mRNA about fifteen-fold, whilst the divalent cation cobalt (50-100 microM) or the iron chelator desferrioxamine (10-200 microM) did not increase EPO mRNA levels. Addition of hydrogen peroxide (100-500 microM) to the culture medium did also not change EPO mRNA levels at high or low oxygen tension. Addition of catalase (50-200 micrograms/ml) to the culture medium resulted in a lower level of hypoxia-induced EPO mRNA. Inhibition of protein synthesis by cycloheximide (100 microM) completely abolished the increase of EPO mRNA in response to hypoxia. Hypoxia but not cobalt increased the appearance of the hypoxia-inducible factor 1 (HIF-1), and this increase was blunted by cycloheximide. Taken together, these findings suggest that a classic heme protein and a related oxygen-dependent production of oxygen radicals is less likely to be involved in the regulation of the EPO gene by oxygen in hepatocytes. On the other hand, intact protein synthesis is an absolute requirement for the hypoxia-induced appearance of HIF-1 and for hypoxia-stimulated expression of the EPO gene in hepatocytes.

Animals↗

PubMed1996

Influence of hypoxia on hepatic and renal endothelin gene expression.

This study aimed to investigate the influence of different forms of tissue hypoxia on the expression of the endothelin genes in kidneys and livers. Tissue hypoxia in rats was induced by five different manoeuvres, namely hypoxia (8% O2), functional anaemia (0.1% CO), haemorrhage (haematocrit, hct = 0.12), cobalt treatment (60 mg/kg) for 6 h each and renal artery stenosis (0.2-mm clips) for 2 days. Endothelin-1 (ET-1) mRNA levels in the kidneys were increased by 200% with renal artery stenosis, 70% by hypoxia, 50% by anaemia, 30% by CO, but were not changed by cobalt. ET-3 mRNA in the kidneys decreased during renal artery clipping and cobalt treatment and were not significantly changed under the other conditions. ET-2 mRNA was not detected in the kidneys and livers. The abundance of ET-1 in the livers of normoxic animals was about 15% of that found in the kidney. Hypoxia increased ET-1 mRNA by 200%, haemorrhage by 400%, whilst CO and cobalt did not change hepatic ET-1 gene expression. The abundance of ET-3 mRNA in the livers of normoxic animals was about 6% of that found in the kidneys. The expression of the ET-3 gene in the livers was decreased by CO, but was not changed by any of the other experimental conditions used. These findings suggest that hyoxaemia and tissue hypoxia are moderate stimuli for the expression of the ET-1 gene but not for the ET-3 gene in the kidney and more potent stimuli in the liver, whilst cobalt does not activate ET-1 gene expression in the kidneys nor the livers.

Anemia↗

PubMed1996

Divergent regulation of vascular endothelial growth factor and of erythropoietin gene expression in vivo.

There is accumulating evidence from in vitro experiments that the gene expression of the vascular endothelial growth factor (VEGF) is, like that of the erythropoietin (EPO) gene, regulated by the oxygen tension and by divalent cations such as cobalt. Since the information about the regulation of VEGF gene expression in vivo is rather scarce, this study aimed to examine the influence of hypoxia and of cobalt on VEGF gene expression in different rat organs and to compare it with that on EPO gene expression. To this end male Sprague-Dawley rats were exposed to carbon monoxide (0.1% CO), hypoxia (8% O2 ) or to cobalt chloride (12 and 60 mg/kg s.c.) for 6 h. mRNA levels for VEGF- 188, -164, and -120 amino acid isoforms in lungs, hearts, kidneys and livers were semiquantitated by RNase protection. For these organs we found a rank order of VEGF mRNA abundance of lung >> heart > kidney = liver. EPO mRNA levels were semiquantitated in kidneys and livers. Hypoxia, CO and cobalt increased EPO mRNA levels 60-fold, 140-fold and 5-fold, respectively, in the kidneys, and 11-fold, 11-fold and 3-fold, respectively, in the livers. None of these manoeuvres caused significant changes of VEGF mRNA in lung, heart or kidneys. Only in the livers did hypoxia lead to a significant (50%) increase of VEGF mRNA. These findings suggest that, in contrast to the in vitro situation, the expression of the VEGF gene in normal rat tissues is rather insensitive to hypoxia. In consequence, the in vivo regulation of the VEGF and the EPO genes appear to differ substantially, suggesting that the regulation of the VEGF and EPO genes may not follow the same essential mechanisms in vivo.

Animals↗