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Pharmacological HIF-PHD inhibition reduces renovascular resistance and increases glomerular filtration by stimulating nitric oxide generation.
Burmakin, Mikhail; Fasching, Angelica; Kobayashi, Hanako; Urrutia, Andrés A; Damdimopoulos, Anastasios; Palm, Fredrik; Haase, Volker H.
Afiliación
  • Burmakin M; Section of Integrative Physiology, Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden.
  • Fasching A; Section of Integrative Physiology, Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden.
  • Kobayashi H; Department of Medicine, Vanderbilt University Medical Center and Vanderbilt University School of Medicine, Nashville, TN, USA.
  • Urrutia AA; Unidad de Investigación Hospital de Santa Cristina, Instituto de Investigación del Hospital Universitario La Princesa, Universidad Autónoma de Madrid, Madrid, Spain.
  • Damdimopoulos A; Bioinformatics and Expression Analysis Core Facility, Department of Biosciences and Nutrition, Karolinska Institute, Stockholm, Sweden.
  • Palm F; Section of Integrative Physiology, Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden.
  • Haase VH; Section of Integrative Physiology, Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden.
Acta Physiol (Oxf) ; 233(1): e13668, 2021 09.
Article en En | MEDLINE | ID: mdl-33900001
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.
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Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Fenómenos Biológicos / Insuficiencia Renal Crónica Tipo de estudio: Observational_studies / Prevalence_studies / Prognostic_studies / Risk_factors_studies Límite: Animals Idioma: En Revista: Acta Physiol (Oxf) Asunto de la revista: FISIOLOGIA Año: 2021 Tipo del documento: Article País de afiliación: Suecia

Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Fenómenos Biológicos / Insuficiencia Renal Crónica Tipo de estudio: Observational_studies / Prevalence_studies / Prognostic_studies / Risk_factors_studies Límite: Animals Idioma: En Revista: Acta Physiol (Oxf) Asunto de la revista: FISIOLOGIA Año: 2021 Tipo del documento: Article País de afiliación: Suecia