Dose-dependent effect of angiotensin II on human erythropoietin production

Freudenthaler, S.M.; Lucht, Ilka; Schenk, Tim; Brink, Marijke; Gleiter, Christoph H.

doi:10.1007/s004240051012

Cited by 20 publications

(30 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The application of the AT1-receptor blocker losartan inhibited the rise of Epo levels, whereas ACE inhibitors did not [17,18]. Later, these findings were confirmed by others [19].…”

Section: Introductionsupporting

confidence: 78%

“…This was regarded a clinically relevant change of Epo concentrations based on the results of our earlier studies [17,18]. The standard error was assumed to be 33%.…”

Section: Discussionmentioning

confidence: 99%

“…As in earlier studies [4][5][6][7]18], the following commercially available assay kits were used. Epo in plasma was analysed using a monoclonal enzyme-linked immunosorbent assay (ELISA, catalogue no.…”

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

Do alterations of endogenous angiotensin II levels regulate erythropoietin production in humans?

Freudenthaler¹,

Benöhr

Grenz

et al. 2003

Brit J Clinical Pharma

View full text Add to dashboard Cite

Aims Recent evidence suggests a potential role of angiotensin II in the physiological regulation of erythropoietin (Epo) production. While the administration of exogenous angiotensin II (AII) has been used so far to study its effects, the role of endogenous AII has remained unclear. Methods To alter endogenous AII in humans experimentally we used furosemide bolus injection as a short-term (study 1) and dietary salt as a long-term modulator (study 2). In an open crossover design, 12 healthy male volunteers received furosemide (F) 0.5 mg kg -1 intravenously or placebo (P) in random order (study 1). With the same design, 12 volunteers received high-salt (HS), normal-salt (NS) and lowsalt (LS) diet (study 2). Plasma renin activity (PRA) was analysed along with AII. Inulin and paraaminohippurate (PAH) clearances were used to indicate glomerular filtration rate (GFR) and renal plasma flow (RPF), respectively. Results While F stimulated AII and PRA and decreased GFR and RPF significantly, no concomitant alteration of Epo was observed [AUCEpo: placebo 5709 ± 243 (% of baseline ¥ h), furosemide: 5833 ± 255 (% of baseline ¥ h); 95% confidence interval (CI) -608.4, 856.0; P = 0.73]. F decreased GFR (from 103.6 ± 4.0 to 90.6 ± 4.8 ml min -1 1 -1 73 m -2 ; 95% CI 1.1, 24.9; P < 0.05), but not RPF (study 1). Correspondingly, LS stimulated and HS decreased AII and PRA significantly. HS increased GFR and RPF. Again, Epo concentrations were not affected (AUCEpo: normal sodium 44 ± 6.7 mIU ¥ day ml -1 , low sodium 39 ± 2.4 mIU ¥ day ml -1 , high sodium 48.5 ± 6.1 mIU ¥ day ml -1 ; normal salt/low salt 95% CI -11.9, 21.9, P = 0.54; normal salt/high salt 95% CI -14.4, 23.3, P = 0.63; study 2). Conclusions We conclude that, at least in the physiological setting in healthy volunteers, increased concentrations of endogenous AII may not be a major factor of Epo regulation.

show abstract

“…The application of the AT1-receptor blocker losartan inhibited the rise of Epo levels, whereas ACE inhibitors did not [17,18]. Later, these findings were confirmed by others [19].…”

Section: Introductionsupporting

confidence: 78%

“…This was regarded a clinically relevant change of Epo concentrations based on the results of our earlier studies [17,18]. The standard error was assumed to be 33%.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Do alterations of endogenous angiotensin II levels regulate erythropoietin production in humans?

Freudenthaler¹,

Benöhr

Grenz

et al. 2003

Brit J Clinical Pharma

View full text Add to dashboard Cite

show abstract

“…Importantly, Ang II has also been implicated in EPO regulation in vivo. Clinical studies of healthy human volunteers demonstrated that Ang II administration increased serum EPO concentration by ∼35% or higher via the activation of the angiotensin II type 1 receptor (AT 1 R) (Freudenthaler et al, 1999(Freudenthaler et al, , 2000Gossmann et al, 2001). Furthermore, the Ang II-converting enzyme inhibitors captopril and enalapril that block the maturation of Ang II from Ang I, significantly decreased plasma EPO levels, by as much as ∼20-30% in another study of healthy human volunteers (Pratt et al, 1992).…”

Section: Introductionmentioning

confidence: 99%

Mechanism of Erythropoietin Regulation by Angiotensin II

Kim

Mungunsukh

McCart

et al. 2014

Molecular Pharmacology

View full text Add to dashboard Cite

Erythropoietin (EPO) is the primary regulator of red blood cell development. Although hypoxic regulation of EPO has been extensively studied, the mechanism(s) for basal regulation of EPO are not well understood. In vivo studies in healthy human volunteers and animal models indicated that angiotensin II (Ang II) and angiotensin converting enzyme inhibitors regulated blood EPO levels. In the current study, we found that Ang II induced EPO expression in situ in murine kidney slices and in 786-O kidney cells in culture as determined by reverse transcription polymerase chain reaction. We further investigated the signaling mechanism of Ang II regulation of EPO in 786-O cells. Pharmacological inhibitors of Ang II type 1 receptor (AT 1 R) and extracellular signal-regulated kinase 1/2 (ERK1/2) suppressed Ang II transcriptional activation of EPO. Inhibitors of AT 2 R or Src homology 2 domain-containing tyrosine phosphatase had no effect. Coimmunoprecipiation experiments demonstrated that p21Ras was constitutively bound to the AT 1 R; this association was increased by Ang II but was reduced by the AT 1 R inhibitor telmisartan. Transmembrane domain (TM) 2 of AT 1 R is important for G protein-dependent ERK1/2 activation, and mutant D74E in TM2 blocked Ang II activation of ERK1/2. Ang II signaling induced the nuclear translocation of the Egr-1 transcription factor, and overexpression of dominant-negative Egr-1 blocked EPO promoter activation by Ang II. These data identify a novel pathway for basal regulation of EPO via AT 1 R-mediated Egr-1 activation by p21Ras-mitogen-activated protein kinase/ERK kinase-ERK1/2. Our current data suggest that Ang II, in addition to regulating blood volume and pressure, may be a master regulator of erythropoiesis.

show abstract

“…Studies in human volunteers demonstrated that elevation of plasma renin activity (PRA) and thus AII levels, as well as intravenous infusion of AII, elevated EPO concentrations in a dose-dependent manner. These effects were greatly reduced by administration of the AII receptor antagonist losartan (Freudenthaler et al, 1999a(Freudenthaler et al, , 2000Gossmann et al, 2001). However, alteration of endogenous angiotensin II levels following high-(HS) and low-salt (LS) diet showed no effect on EPO secretion in healthy volunteers (Freudenthaler et al, 2003), whereas high-salt diet increased EPO concentrations in essential hypertensive patients (Naomi et al, 1993).…”

mentioning

confidence: 99%

Role of Renal Nerves and Salt Intake on Erythropoietin Secretion in Rats following Carbon Monoxide Exposure

Gebhard

Petroktistis²,

Zhang³

et al. 2006

J Pharmacol Exp Ther

View full text Add to dashboard Cite

Because the data from the literature contain conflicting results regarding the role of renal nerves and angiotensin II in hypoxiainduced erythropoietin (EPO) secretion, we evaluated the effect of renal nerves and salt intake in rats on EPO secretion stimulated by carbon monoxide (CO). Serum levels and renal mRNA content of EPO were similarly elevated by exposure to different CO concentrations in a dose-dependent manner in rats with bilateral renal denervation (DNX) and in sham-denervated controls (INN). However, at 600 ppm CO, serum concentrations and mRNA of EPO were significantly higher in DNX compared with INN rats (p Ͻ 0.05). This increase of EPO secretion in DNX rats could be blocked by administration of neuropeptide Y (NPY) (p Ͻ 0.05), whereas the NPY receptor antagonist did not enhance EPO secretion in INN rats after CO exposure. Agonists and antagonists of ␤-adrenergic receptors had no effect on EPO secretion. High-salt (HS) diet reduced EPO secretory response at 600 ppm CO by 55% compared with INN rats on normal salt diet (p Ͻ 0.01). In addition, DNX increased EPO secretion in rats on low-salt and HS diet, whereas plasma renin activity did not correlate with EPO levels under these experimental conditions. In summary, our data suggest that renal nerves contribute to the half-maximal EPO secretory response to CO exposure, possibly via NPY receptors.Erythropoietin (EPO), a glycoprotein hormone, is an essential growth factor that regulates erythropoiesis, and in adult laboratory animals and in humans, it is predominantly synthesized in the kidneys (Jelkmann, 1992;Jelkmann and Metzen, 1996). EPO secretion and renal mRNA content are inversely correlated to renal oxygen supply (Scholz et al., 1991). Because renal ischemia in isolated perfused kidneys elicited a much weaker EPO secretory response compared with systemic hypoxia in vivo, it was postulated that additional factors such as nerves and humoral factors may contribute to EPO secretory response to hypoxia (Pagel et al., 1989).Despite that multiple studies have investigated the role of renal nerves on EPO secretion, the published data are contradictory. Beynon (1977). reported increased EPO levels in rats exposed to 6 h of hypoxia (10% O 2 ) following denervation (DNX) of the left kidney and after contralateral nephrectomy compared with control rats with intact renal nerves. In contrast Fink and Fisher (1976) found reduced EPO levels in rabbits exposed to 5 h of hypoxia (0.42 atmospheres) following bilateral renal denervation in control animals. Eckardt et al. (1992) showed in rats that denervation of one kidney does not effect EPO mRNA following systemic exposure to hypoxia, hemorrhage, and carbon monoxide (CO) compared with the contralateral innervated control kidney.Moreover, combination of renal denervation and ␤-adrenergic receptor blockade showed to inhibit the hypoxia-stimulated EPO secretion compared with controls (Fink and Fisher, 1976). However, Jelkmann et al. (1979) could not confirm these findings, since his group reported unchanged ...

show abstract

Dose-dependent effect of angiotensin II on human erythropoietin production

Cited by 20 publications

References 21 publications

Do alterations of endogenous angiotensin II levels regulate erythropoietin production in humans?

Do alterations of endogenous angiotensin II levels regulate erythropoietin production in humans?

Mechanism of Erythropoietin Regulation by Angiotensin II

Role of Renal Nerves and Salt Intake on Erythropoietin Secretion in Rats following Carbon Monoxide Exposure

Contact Info

Product

Resources

About