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Pharmacological HIF‐PHD inhibition reduces renovascular resistance and increases glomerular filtration by stimulating nitric oxide generation.

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Title: Pharmacological HIF‐PHD inhibition reduces renovascular resistance and increases glomerular filtration by stimulating nitric oxide generation.
Authors: Burmakin, Mikhail (AUTHOR), Fasching, Angelica (AUTHOR), Kobayashi, Hanako (AUTHOR), Urrutia, Andrés A. (AUTHOR), Damdimopoulos, Anastasios (AUTHOR), Palm, Fredrik (AUTHOR), Haase, Volker H. (AUTHOR)
Source: Acta Physiologica. Sep2021, Vol. 233 Issue 1, p1-14. 14p. 1 Diagram, 2 Charts, 6 Graphs.
Subjects: Hypoxia-inducible factors, Nitric oxide, Glomerular filtration rate, Small molecules, Chronic kidney failure, Transcription factors
Abstract: Aim: Hypoxia‐inducible factors (HIFs) are O2‐sensitive transcription factors that regulate multiple biological processes which are essential for cellular adaptation to hypoxia. Small molecule inhibitors of HIF‐prolyl hydroxylase domain (PHD) dioxygenases (HIF‐PHIs) activate HIF‐dependent transcriptional programs and have broad clinical potential. HIF‐PHIs are currently in global late‐stage clinical development for the treatment of anaemia associated with chronic kidney disease. Although the effects of hypoxia on renal haemodynamics and function have been studied in animal models and in humans living at high altitude, the effects of pharmacological HIF activation on renal haemodynamics, O2 metabolism and metabolic efficiency are not well understood. Methods: Using a cross‐sectional study design, we investigated renal haemodynamics, O2 metabolism, gene expression and NO production in healthy rats treated with different doses of HIF‐PHIs roxadustat or molidustat compared to vehicle control. Results: Systemic administration of roxadustat or molidustat resulted in a dose‐dependent reduction in renovascular resistance (RVR). This was associated with increased glomerular filtration rate (GFR), urine flow and tubular sodium transport rate (TNa). Although both total O2 delivery and TNa were increased, more O2 was extracted per transported sodium in rats treated with high‐doses of HIF‐PHIs, suggesting a reduction in metabolic efficiency. Changes in RVR and GFR were associated with increased nitric oxide (NO) generation and substantially suppressed by pharmacological inhibition of NO synthesis. Conclusions: Our data provide mechanistic insights into dose‐dependent effects of short‐term pharmacological HIF activation on renal haemodynamics, glomerular filtration and O2 metabolism and identify NO as a major mediator of these effects. [ABSTRACT FROM AUTHOR]
Copyright of Acta Physiologica is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
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  Label: Title
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  Data: Pharmacological HIF‐PHD inhibition reduces renovascular resistance and increases glomerular filtration by stimulating nitric oxide generation.
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  Data: <searchLink fieldCode="AR" term="%22Burmakin%2C+Mikhail%22">Burmakin, Mikhail</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Fasching%2C+Angelica%22">Fasching, Angelica</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Kobayashi%2C+Hanako%22">Kobayashi, Hanako</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Urrutia%2C+Andrés+A%2E%22">Urrutia, Andrés A.</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Damdimopoulos%2C+Anastasios%22">Damdimopoulos, Anastasios</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Palm%2C+Fredrik%22">Palm, Fredrik</searchLink> (AUTHOR)<br /><searchLink fieldCode="AR" term="%22Haase%2C+Volker+H%2E%22">Haase, Volker H.</searchLink> (AUTHOR)
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  Data: <searchLink fieldCode="JN" term="%22Acta+Physiologica%22">Acta Physiologica</searchLink>. Sep2021, Vol. 233 Issue 1, p1-14. 14p. 1 Diagram, 2 Charts, 6 Graphs.
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  Data: <searchLink fieldCode="DE" term="%22Hypoxia-inducible+factors%22">Hypoxia-inducible factors</searchLink><br /><searchLink fieldCode="DE" term="%22Nitric+oxide%22">Nitric oxide</searchLink><br /><searchLink fieldCode="DE" term="%22Glomerular+filtration+rate%22">Glomerular filtration rate</searchLink><br /><searchLink fieldCode="DE" term="%22Small+molecules%22">Small molecules</searchLink><br /><searchLink fieldCode="DE" term="%22Chronic+kidney+failure%22">Chronic kidney failure</searchLink><br /><searchLink fieldCode="DE" term="%22Transcription+factors%22">Transcription factors</searchLink>
– Name: Abstract
  Label: Abstract
  Group: Ab
  Data: Aim: Hypoxia‐inducible factors (HIFs) are O2‐sensitive transcription factors that regulate multiple biological processes which are essential for cellular adaptation to hypoxia. Small molecule inhibitors of HIF‐prolyl hydroxylase domain (PHD) dioxygenases (HIF‐PHIs) activate HIF‐dependent transcriptional programs and have broad clinical potential. HIF‐PHIs are currently in global late‐stage clinical development for the treatment of anaemia associated with chronic kidney disease. Although the effects of hypoxia on renal haemodynamics and function have been studied in animal models and in humans living at high altitude, the effects of pharmacological HIF activation on renal haemodynamics, O2 metabolism and metabolic efficiency are not well understood. Methods: Using a cross‐sectional study design, we investigated renal haemodynamics, O2 metabolism, gene expression and NO production in healthy rats treated with different doses of HIF‐PHIs roxadustat or molidustat compared to vehicle control. Results: Systemic administration of roxadustat or molidustat resulted in a dose‐dependent reduction in renovascular resistance (RVR). This was associated with increased glomerular filtration rate (GFR), urine flow and tubular sodium transport rate (TNa). Although both total O2 delivery and TNa were increased, more O2 was extracted per transported sodium in rats treated with high‐doses of HIF‐PHIs, suggesting a reduction in metabolic efficiency. Changes in RVR and GFR were associated with increased nitric oxide (NO) generation and substantially suppressed by pharmacological inhibition of NO synthesis. Conclusions: Our data provide mechanistic insights into dose‐dependent effects of short‐term pharmacological HIF activation on renal haemodynamics, glomerular filtration and O2 metabolism and identify NO as a major mediator of these effects. [ABSTRACT FROM AUTHOR]
– Name: AbstractSuppliedCopyright
  Label:
  Group: Ab
  Data: <i>Copyright of Acta Physiologica is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
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        Value: 10.1111/apha.13668
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        Type: general
      – SubjectFull: Nitric oxide
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      – SubjectFull: Glomerular filtration rate
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      – SubjectFull: Small molecules
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      – SubjectFull: Chronic kidney failure
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      – TitleFull: Pharmacological HIF‐PHD inhibition reduces renovascular resistance and increases glomerular filtration by stimulating nitric oxide generation.
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              M: 09
              Text: Sep2021
              Type: published
              Y: 2021
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