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A Kurtz

Publications and source records attributed to A Kurtz.

At least 127 records · Page 7Linked to original sources
PubMed1995

Renin gene and angiotensin II AT1 receptor gene expression in the kidneys of normal and of two-kidney/one-clip rats.

This study aimed to investigate the inter-relation between the angiotensin II (ANG II) AT1 receptor and renin gene expression in rat kidneys. To this end, renin mRNA levels and mRNA levels for AT1a and AT1b were assayed by RNase protection in the kidneys of normal rats, in animals treated with the AT1 antagonist losartan and in rats bearing 0.2-mm left renal artery clips for 2 days. In normal rats, we found a negative correlation between renin mRNA levels and AT1a receptor mRNA levels. Losartan led to a fourfold increase in renin mRNA levels without changing AT1 receptor mRNA levels. Unilateral renal artery clipping increased renin mRNA levels fourfold in the clipped kidney and suppressed renin mRNA levels in the contralateral kidneys. AT1 receptor mRNA levels were not changed in the contralateral intact kidneys, but were significantly decreased by 15-25% in the clipped kidneys. Renin mRNA levels were inversely correlated to AT1a mRNA levels in the clipped, but not in the contralateral, kidneys. Our findings suggest that the systemic activity of the renin angiotensin system has no regulatory influence on renal AT1 receptor gene expression. Renin mRNA levels in normal and in clipped kidneys appear to be negatively determined by the level of AT1a receptor gene expression. Thus modulation of AT1a receptor gene expression could be a pathway for indirect modulation of renin gene expression by ANG II. This conclusion is in agreement with the observation that AT1 receptor antagonists are powerful stimulators of the renin system.

Angiotensin Receptor Antagonists↗
PubMed1995

Opposite regulation of renin gene expression by cyclic AMP and calcium in isolated mouse juxtaglomerular cells.

A quantitative reverse transcriptase-polymerase chain reaction for mouse renin mRNA was utilized to study the influence of classic second messenger molecules on renin mRNA levels in primary cultures of juxtaglomerular (JG) cells isolated from the kidneys of C57/B16 mice. We found that forskolin (3 microM), an activator of adenylate cyclase led to proportional increases of renin secretion and renin mRNA levels. The nitric oxide (NO) donor, sodium nitroprusside (100 microM), stimulated both renin secretion and renin gene expression, the effect on secretion being stronger than that on renin mRNA levels. An increase of the extracellular concentration of calcium from 0.5 to 3 mM led to a transient inhibition of renin secretion, followed by a marked stimulation of secretion and to a continuous suppression of renin mRNA levels. These were also decreased by the calcium ionophore A 23187 (1 microM). The membrane permeable 8-bromo-cyclic GMP (100 microM) inhibited basal renin secretion without an effect on renin mRNA levels. The phorbol ester phorbol-12-myristate-13-acetate (1 to 100 nM), which was used to stimulate protein kinase C activity, had no significant effects on renin secretion and renin mRNA levels, neither alone nor in combination with forskolin. These findings suggest that cAMP, NO and calcium are effective regulators of renin gene expression in renal JG cells, in a way that cAMP and NO are stimulators and calcium acts as an inhibitor. Moreover, in these acute experiments there appears to be no obligatory link between the secretion and the expression of renin, suggesting that both parameters are separately regulated.

Animals↗
PubMed1995

Occupational environment as risk factor for unemployment in multiple sclerosis.

INTRODUCTION: Few studies have examined the factors of occupational environment related to unemployment in multiple sclerosis (MS). MATERIAL AND METHODS: A case control-study was carried out. Cases were patients unemployed for less than five years before the study (n = 77); controls were patients currently employed (n = 94). The odds ratios of the relationship under study adjusted for sex, age, disease form and educational level, were estimated. RESULTS: Employment in the public sector, sedentary jobs and possibility of obtaining specific improvements in the work environment were found to be protective factors, while jobs needing force, rigid work schedule, manual precision, frequent moves and a daily work duration over 8 h were found as risk factors. Multivariate analyses showed that the only remaining factors were public sector jobs as protective factor (OR = 0.4), and strenuous work as risk factor (OR = 4.5). Factors were slightly different in male and female patients. CONCLUSION: This study suggests that simple and early changes in the occupational environment could maintain MS patients at work.

Adult↗
PubMed1995

Effects of endothelins on renin secretion from rat kidneys.

Using a preparation of isolated rat kidneys perfused at constant renal artery pressure (80 mmHG) we investigated the role of endothelins in the regulation of renin release. Addition of three related endothelins (ET-1, ET-2, ET-3) at a concentration of 10 pmol L(-1) tended to enhance renin secretion rates. Higher doses (100 pmol L(-1), 1 nmol L(-1)) of different ETs such as the selective ETB receptor agonist sarafotoxin S6c (100 pmol L(-1), 1 nmol L(-1)) inhibited renin release and increased renal vascular resistance with similar potency. These effects of ETs were blunted when calcium ions were removed from the perfusate. Renin release activated by isoproterenol (10 nmol L(-1)) was also significantly reduced with ET-1, -2 and -3 (1 nmol L(-1)). BQ-123 (500 nmol L(-1)), a selective ETA receptor antagonist, only attenuated, whilst the non-selective ET receptor blocker bosentan (Ro 47-0203, 10 micro mol L(-1)) almost abolished the renal vasopressor and renin inhibitory action of ET-1 and sarafotoxin S6c. BQ-123 and bosentan alone did not affect either perfusate flow or basal renin secretion rates in isolated perfused kidneys. These findings indicate that all three ET peptides equipotently inhibit renin secretion from the kidneys. Most of the vasopressor and renin inhibitory effect of ETs is mediated by ETB rather than ETA receptors involving a calcium-dependent signal transduction mechanism. Moreover, our results suggest that intrarenally released ETs do not contribute to the regulation of renin secretion from isolated perfused rat kidneys.

Animals↗
PubMed1995

Cobalt exerts opposite effects on erythropoietin gene expression in rat hepatocytes in vivo and in vitro.

This study investigates the effects of hypoxia and of cobalt on erythropoietin (EPO) gene expression in hepatocytes in vivo and in vitro in neonatal, juvenile, and adult rats. With the use of the ribonuclease protection assay to quantify RNA, both hypoxia (0.1% CO or 9% O2) and cobalt (60 mg/kg) elicit production of increased amounts of EPO mRNA in neonatal and juvenile rat liver in vivo. In vitro hepatocyte EPO gene expression could be reproducibly stimulated by hypoxia (3% O2) but not by cobaltous chloride (50-150 microM) within 2-20 h. Conversely, cobalt substantially attenuated the rise of EPO mRNA levels in response to hypoxia. This inhibitory effect of cobalt was mimicked by zinc but not by other metals. CO attenuated the rise of EPO mRNA levels in vitro in response to hypoxia; this inhibitory effect coincided with an inhibition of total RNA synthesis as determined by [3H]uridine incorporation. The lack of specific inhibitory effects of CO and of specific stimulatory effects of cobalt on hepatocyte EPO gene expression in vitro suggests that a specific heme oxygen sensor may be less important than in hepatoma cells.

Animals↗
PubMed1995

Effects of endothelins on renin secretion from isolated mouse renal juxtaglomerular cells.

This study was performed to examine the effects of endothelin (ET)-1, ET-2, and ET-3 on renin secretion from cultured mouse renal juxtaglomerular (JG) cells. Although different ETs had no consistent effect on basal renin secretion, they equipotently inhibited adenosine 3',5'-cyclic monophosphate (cAMP)-stimulated renin release with a concentration of approximately 3 nM inhibiting 50% of maximal response. ETs did not significantly affect renin release stimulated by the nitric oxide donor sodium nitroprusside (100 microM) or that stimulated by low [2 mM ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid] or high (3 mM CaCl2) extracellular calcium. The inhibitory effect of ETs on cAMP-dependent renin secretion was abolished by lowering extracellular calcium concentration to the nanomolar range. However, the action of ETs was not changed by the ETA receptor antagonist BQ-123 (100 nM) and was mimicked by ETB receptor agonists IRL-1620 (1 microM), sarafotoxin S6b (1 microM), and [Ala1,3,11,15]ET-1 (1 microM). All ETs induced calcium oscillations in JG cells that were dependent on extracellular calcium and were associated with prominent calcium-activated chloride currents. These findings suggest that ETs inhibit rather selectively the cAMP-activated pathway of renin secretion through a calcium-sensitive process. The action of ETs on renal JG cells appears to be mediated via ETB receptors and is presumably related to activation of phospholipase C and subsequent events.

Animals↗
PubMed1995

Role of membrane-permeable ions in renin secretion by renal juxtaglomerular cells.

In this study we examine the role of membrane-permeable ions in renin secretion from renal juxtaglomerular (JG) cells. To this end, extracellular Cl- (100 mmol/l) in the culture medium of isolated mouse renal JG cells was replaced by the permeable anion NO3- or by the membrane-impermeable anion isethionate. Alternatively, extracellular Na+ (100 mmol/l) was substituted by the membrane-impermeable cation choline. The effects of these ion substitutions on basal and stimulated renin secretion were then examined. Renin secretion was stimulated by the adenylate cyclase activator forskolin (10 microM), the NO donor sodium nitroprusside (SNP, 100 microM), the calmodulin antagonist calmidazolium (10 microM), by lowering extracellular Ca2+ concentration ([Ca2+]e) with ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA) (2 mM), and by increasing [Ca2+]e from the normal value of 0.5 to 3 mM. Substitution of extracellular Cl- by isethionate, but not by NO3-, inhibited basal renin release over 20 h of incubation. NO3- also did not change renin secretion stimulated by forskolin, SNP, calmidazolium, EGTA, or by increased [Ca2+]e. Isethionate, on the other hand, markedly attenuated the effects of EGTA and of increased [Ca2+]e, but not the stimulatory effect of forskolin, calmidazolium, or SNP. Substitution of Na+ by choline also attenuated basal renin secretion and renin secretion stimulated by lowering or raising [Ca2+]e. These findings suggest that, with respect to the dependency on permeable ions, at least two different pathways of regulated renin secretion from JG cells exist: a cation- and anion-dependent Ca(2+)-related pathway and a less ion-sensitive pathway for renin secretion activated by adenosine 3',5'-cyclic monophosphate and NO.

Animals↗
PubMed1995

Expression of endothelins 1 and 3 in the rat kidney.

Endothelins (ETs) 1 and 3 are expressed in the rat kidney, but the factors that regulate this expression remain unknown. To try to understand what these might be, we have measured the renal levels of ET-1 and ET-3 mRNAs by the ribonuclease protection-assay technique after a number of clearly defined renal/hemodynamic insults. 1) Six hours after the induction of hemorrhagic anemia and hypotension, there was a threefold increase in ET-1 mRNA and a simultaneous threefold decrease in ET-3 mRNA. This indicates that, in this situation, these two ET isoforms are differentially controlled and emphasizes the need for assay techniques capable of distinguishing between them. 2) One day after application of a 0.2-mm clip to the left renal artery, there was a > 2.5-fold induction of ET-1 mRNA in that kidney, which persisted for 10 days. A smaller rise in ET-1 mRNA was seen in the contralateral organ. After 2 days, ET-3 mRNA levels were reduced by approximately 50% in the clipped organ. Both ramipril (an angiotensin-converting enzyme inhibitor, 7.5 mg/kg daily) and bosentan (a nonselective ET receptor antagonist, 100 mg/kg daily) substantially reduced the elevation in ET-1 mRNA seen in the clipped kidney after 2 days, suggesting that the generation of angiotensin II and the action of ET itself are involved in the mechanism by which clipping stimulates ET-1 expression. By contrast, ramipril, but not bosentan, prevented the reduction in ET-3 mRNA levels. 3) Renal denervation, dietary salt restriction, or diuretic treatment (furosemide) did not alter renal expression of ET-1 or ET-3.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Nitric oxide and prostaglandins are involved in the macula densa control of the renin system.

This study sought to examine the involvement of prostaglandins and of nitric oxide (NO) in the macula densa-dependent activation of the renin system in vivo. For this purpose, male Sprague-Dawley rats were chronically infused with furosemide (12 mg/day) for 6 days to inhibit macula densa salt transport. To inhibit the synthesis of prostaglandins and of NO, animals were injected with indomethacin (2 mg/kg twice daily) and with nitro-L-arginine methyl ester (L-NAME; 40 mg/kg twice daily) for the last 2 days of the experiment, respectively. Furosemide infusion increased plasma renin activity (PRA) from 8.8 +/- 1.4 to 41 +/- 5.2 ng angiotensin I (ANG I).h-1.ml-1 and renin mRNA levels from 112 +/- 8 of standard to 249 +/- 18% of standard. After treatment with indomethacin, the furosemide-induced increases in renin mRNA levels was attenuated to 190 +/- 11% of standard. After injections of L-NAME, both the furosemide-induced increases of renin mRNA levels and of PRA were reduced to 126 +/- 14% of standard and 22 +/- 5 ng ANG I.h-1.ml-1, respectively. These findings suggest that activation of renin gene expression by blockade of the macula densa function is dependent on intact NO and prostaglandin formation, whereas for stimulation of renin secretion mainly intact NO formation appears to be necessary.

Angiotensin I↗
PubMed1995

No acute change of serum erythropoietin in response to hypocalcemia or antihypertensive agents in uremic patients.

Endogenous erythropoietin (EPO) secretion can still be modulated in patients with end-stage renal failure but only in response to strong stimuli. Thus even anephric dialysis patients are able to increase EPO production acutely when exposed to a marked hypoxic stimulus. The present study was designed to test the hypothesis that a decrease of plasma calcium or the administration of various antihypertensive agents might be able to induce acute changes of plasma EPO concentration. Four groups of chronic hemodialysis patients were studied. Eight patients volunteered for the induction of an acute, transient hypocalcemia via a calcium-free dialysate during the initial 60 min of a regular dialysis session of 240 min. Plasma immunoreactive (i) EPO, total calcium, and intact parathyroid hormone (iPTH1-84), as well as blood ionized calcium and blood gases were measured before as well as 30, 60, 120 and 240 min after the start of dialysis. In addition, plasma iEPO was measured 48 h after the session. Patients of group 2 (n = 6), group 3 (n = 6), and group 4 (n = 7) received the day after a hemodialysis session a single dose of either acetazolamide, furosemide, or enalapril, respectively, and their plasma iEPO was determined before and 3, 6 and/or 24 h after drug administration. In group 1, plasma total calcium decreased from 2.39 +/- 0.07 mM (mean +/- SEM) to 1.98 +/- 0.02 and 1.83 +/- 0.03 mM after 30 and 60 min of dialysis, respectively, and blood ionized calcium from 1.28 +/- 0.04 to 1.02 +/- 0.03 and 0.92 +/- 0.04 mM, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1995

Role of endogenous endothelins in the renin system of normal and two-kidney, one clip rats.

This study aimed to investigate the relevance of endogenous endothelins in the control of renin secretion and renin gene expression under basal conditions and stimulated conditions achieved with unilateral renal artery stenosis. To this end, we studied the effects of the orally active endothelin antagonist Ro 47-0203 (100 mg/kg per day) for 2 days on plasma renin activity and renal renin mRNA levels in normal rats and rats with unilateral renal artery clips (0.2 mm). Treatment with Ro 47-0203 did not change basal arterial pressure but significantly attenuated the rise of blood pressure in response to renal artery clipping. Although Ro 47-0203 tended to increase basal plasma renin activity, this effect was not significant. Basal renin mRNA levels of kidneys were also not changed by the drug. Unilateral renal artery clipping increased plasma renin activity from 12 to 34 ng angiotensin I/mL per hour, increased renin mRNA levels to 328% of controls in the clipped kidneys, and decreased renin mRNA levels to 23% of controls in the contralateral intact kidneys. These changes were not influenced by Ro 47-0203. In isolated perfused rat kidneys, Ro 47-0203 (10 mumol/L) also had no effect on basal renin secretion or vascular resistance, but it substantially attenuated the decrease of renin secretion and renal flow in response to administration of exogenous endothelin. Taken together, these findings suggest that endogenous endothelins play no relevant role in the control of renin secretion and of renin gene expression in normal and hypoperfused rat kidneys.

Animals↗
PubMed1995

Renal artery stenosis rapidly enhances atrial natriuretic peptide gene expression.

The aim of this study was to examine the influence of the systemic renin-angiotensin system on the gene expression of atrial natriuretic peptide in rat hearts. The renin-angiotensin system was stimulated (1) by unilateral renal artery clipping (0.2-mm clip, 2 days), producing a fourfold increase of circulating plasma renin activity and increasing blood pressure; (2) by furosemide infusion with simultaneous salt substitution, increasing plasma renin activity values to 45 ng angiotensin I/h per milliliter without changing blood pressure; or (3) by administration of the calcium antagonist amlodipine, which increased plasma renin activity values to 42 ng angiotensin I/h per milliliter and lowered blood pressure. Unilateral renal artery clipping increased atrial natriuretic peptide mRNA levels approximately 20-fold in the left ventricles and approximately twofold in the right ventricles and atria. Furosemide infusion had no effect on cardiac atrial natriuretic peptide mRNA levels, and in amlodipine-treated rats, cardiac atrial natriuretic peptide mRNA levels decreased to 30% of control values. The increase of atrial natriuretic peptide mRNA in the ventricles during renal artery clipping was blunted by the administration of the angiotensin-converting enzyme inhibitor ramipril, which also attenuated the blood pressure rise. In clipped rats amlodipine did not change elevated plasma renin activity values but abolished the rise of blood pressure and also attenuated the rise of atrial natriuretic peptide mRNA in the hearts. These findings indicate that an increase of the activity of the systemic renin-angiotensin system does not result in an obligatory change in cardiac atrial natriuretic peptide gene expression.(ABSTRACT TRUNCATED AT 250 WORDS)

Aldosterone↗
PubMed1995

Expression of cardiac angiotensin II AT1 receptor genes in rat hearts is regulated by steroids but not by angiotensin II.

OBJECTIVE: To examine the regulation by angiotensin II and by steroids of the expression of the angiotensin II AT1a and AT1b receptor genes in rat hearts. METHODS: Endogenous levels of angiotensin II in the rats were increased either by unilateral 0.2-mm renal artery clips or by subcutaneous infusions of frusemide (12 mg/day) and by low-sodium diet. To inhibit endogenous angiotensin II actions the rats received the AT1 receptor antagonist losartan (40 mg/kg per day) or the angiotensin converting enzyme inhibitor ramipril (8 mg/kg per day). Circulating levels of glucocorticoids were elevated by subcutaneous injections of dexamethasone (400 micrograms/kg per day) and levels of mineralocorticoids were increased by subcutaneous injections of deoxycorticosterone acetate (2 mg/kg per day). AT1a and AT1b messenger RNA (mRNA) levels were semiquantified by reverse-transcriptase polymerase chain reaction and related to actin mRNA. RESULTS: The AT1a mRNA:AT1b mRNA ratio in the hearts of untreated rats was 10:1. Unilateral renal artery clipping led to a 30% decrease in AT1a mRNA, whereas treatment with frusemide, losartan or ramipril had no effect on the AT1a or AT1b mRNA levels. Rats fed a low-sodium diet showed a 37% increase in AT1a gene expression. Dexamethasone increased AT1a mRNA by 100% and AT1b mRNA by 300%, whereas deoxycorticosterone acetate treatment decreased AT1a mRNA levels to 30% of the control values. CONCLUSIONS: The present results suggest that the expression of the predominant cardiac AT1a receptor gene is not feedback-regulated by endogenous angiotensin II, whereas steroid hormones appear to be effective regulators, because glucocorticoids stimulate AT1 receptor gene expression and mineralocorticoids inhibit it.

Adrenal Cortex Hormones↗
PubMed1995

Endothelin inhibits cAMP-induced renin release from isolated renal juxtaglomerular cells.

We examined the effects of endothelin (ET)-1, -2, and -3 on renin secretion from cultured mouse renal juxtaglomerular cells. Although different ETs had no consistent effect on basal renin secretion, they equipotently inhibited cAMP-stimulated renin release with an IC50 value of approximately 3 nM. ETs did not significantly affect renin release stimulated by the nitric oxide (NO)-donor nitroprusside (100 microM) or that stimulated by low (2 mM EGTA) or high (3 mM CaCl2) extracellular calcium. The inhibitory effect of ETs on cAMP-dependent renin secretion was abolished by lowering extracellular calcium concentration to the nanomolar range. However, the action of ETs was not changed by the ETA receptor antagonist BQ 123 (100 nM) and was mimicked by the ETB receptor agonists IRL 1620 (1 microM), sarafotoxin S6c (1 microM), and [Ala1,3,11,15]endothelin-1 (4 Ala-ET-1, 1 microM). These findings suggest that ETs selectively inhibit the cAMP-activated pathway of renin secretion through a calcium-sensitive process. The action of ETs on renal juxtaglomerular cells appears to be mediated via ETB receptors.

Animals↗
PubMed1995

Pleiotrophin and midkine in normal development and tumor biology.

Pleiotrophin (PTN) and midkine (MK) are members of a family of developmentally regulated, secreted heparin-binding proteins. The proteins are structural homologs, and are highly conserved among species. Although no homology has been detected with other heparin-binding growth factors, their functional similarity to members of the fibroblast growth factor (FGF) family is remarkable. PTN and MK are expressed during embryogenesis, showing an expression pattern that suggests functions in neurogenesis, cell migration, secondary organogenetic induction, and mesoderm-epithelial interaction. The widespread downregulation of PTN and MK in the adult human is reverted in a number of cancers, in which polypeptides are able to act as both transforming growth factors and promoters of angiogenesis. Elucidating the molecular mechanisms of PTN and MK action could lead not only to a deeper understanding of developmental processes, but also to the ultimate identification of targets for tumor therapy.

Adult↗
PubMed1994

Production of erythropoietin by liver cells in vivo and in vitro.

Several lines of evidence indicate that the liver is the predominant production site for EPO during the early stages of development. Moreover, in adults, it may contribute significantly to EPO production in some species. Independent of age hepatocytes are the major cellular sites of EPO gene expression in the liver, but quantitatively less significant expression also occurs in at least one additional type of nonparenchymal cell. Although some indirect evidence suggests that these nonparenchymal cells producing EPO may be Kupffer cells, their identity remains to be clarified. Regarding the mechanisms of the adaptation of hepatic EPO production to changes in oxygen availability in the organism, experiments with isolated perfused livers, mixed liver cell cultures, hepatoma cells, and, more recently, isolated hepatocytes have provided evidence that inherent cellular oxygen-sensing mechanisms exist and that external factors are not essential. The use of hepatoma cells has allowed investigation of these cellular mechanisms of oxygen-dependent gene control, and further studies in nontransformed hepatocytes may complement these studies.

Aging↗
PubMed1994

Hypoxia-induced accumulation of erythropoietin mRNA in isolated hepatocytes is inhibited by protein kinase C.

To define the role of protein kinase C (PKC) in oxygen-dependent production of erythropoietin (EPO) in the liver, we have determined EPO messenger ribonucleic acid (mRNA) expression in primary cultures of juvenile rat hepatocytes incubated at different oxygen tensions in the absence and presence of phorbol esters, vasopressin, and structurally different kinase inhibitors. Upon reduction of oxygen concentrations from 40% to 3% EPO mRNA in cultured hepatocytes increased markedly within 1.25 h, reached maximal values after 2.5 h and remained elevated for up to 72 h. Treatment of hepatocytes during 1.25-5 h of hypoxic exposure with phorbol 12-myristate-13 acetate (PMA) attenuated hypoxia-induced EPO mRNA levels dose-dependently by a maximum of approximately 50%. This inhibitory effect of PMA disappeared upon treatment for more than 5 h and was completely lost after incubation for 9 and 18 h in the presence of 10(-6) M and 10(-7) M PMA, respectively. Phorbol 12,13-dibutyrate and vasopressin also inhibited EPO mRNA accumulation, whereas 4 alpha-phorbol 12,13-didecanoate was ineffective. Western blot analysis of PKC isozymes revealed the presence of PKC alpha, beta II, delta, epsilon and zeta and provided no evidence that the PMA-induced inhibition of EPO expression was associated with depletion of any of these isozymes. Conversely, PMA-induced inhibition of EPO mRNA accumulation was paralleled by translocation of PKC alpha from cytosol to membranes and the time- and dose-dependent attenuation of the inhibitory effect of PMA on EPO mRNA levels was paralleled by down-regulation of PKC alpha. A dose-dependent inhibition of EPO mRNA formation, independent of effects on total RNA synthesis, as determined by [3H]uridine incorporation, was also found in the presence of the kinase inhibitor staurosporine (ED50 approximately 2 x 10(-8) M) and three structurally related derivatives with increased selectivity for PKC (RO 317549, ED50 approximately 1 x 10(-6) M; RO 318220, ED50 approximately 1 x 10(-6) M and CGP 41251, ED50 approximately 4 x 10(-6) M). The markedly lower potency of the latter three compounds as compared to staurosporine suggests that this suppression of EPO gene induction was not mediated by inhibition of PKC. In summary the data indicate that PKC alpha is a negative modulator of EPO gene expression in hepatocytes. A kinase other than PKC, however, appears to be an essential element of hypoxic signalling.

Alkaloids↗