Increased oxidative stress contributes to impaired hypoxia-inducible factor prolyl-hydroxylase 2 response to high salt in Dahl salt-sensitive rats

Abstract Background: Hypoxia inducible factor (HIF)/prolyl hydroxylase domain (PHD)-containing proteins are involved in renal adaptive response to high salt (HS). Peroxisome proliferator activated receptor alpha (PPARα), a transcription factor involved in fatty acid oxidation is implicated in the regulation of renal function. As both HIF-1α/PHD and PPARα contribute to the adaptive changes to altered oxygen tension, this study tested the hypothesis that PHD-induced renal adaptive response to HS is PPARα-dependent. Methods: PPARα wild type (WT) and knock out (KO) mice were fed a low salt (LS) (0.03% NaCl) or a HS (8% NaCl) diet for 8 days and treated with hydralazine. PPARα and heme oxygenase (HO)-1 expression were evaluated in the kidney cortex and medulla. A 24-h urinary volume (UV), sodium excretion (UNaV), and nitrite excretion (UNOx V) were also determined. Results: PHD1 expression was greater in the medulla as compared to the cortex of PPARα WT mice (p<0.05) fed with a LS (0.03% NaCl) diet. The HS diet (8% NaCl) downregulated PHD1 expression in the medulla (p<0.05) but not the cortex of WT mice whereas expression was downregulated in the cortex (p<0.05) and medulla (p<0.05) of KO mice. These changes were accompanied by HS-induced diuresis (p<0.05) and natriuresis (p<0.05) that were greater in WT mice (p<0.05). Similarly, UNOx V, index of renal nitric oxide synthase (NOS) activity or availability and heme oxygenase (HO)-1 expression was greater in WT (p<0.05) but unchanged in KO mice on HS diet. Hydralazine, a PHD inhibitor, did not affect diuresis or natriuresis in LS diet-fed WT or KO mice but both were increased (p<0.05) in HS diet-fed WT mice. Hydralazine also increased UNOx V (p<0.05) with no change in diuresis, natriuresis, or HO-1 expression in KO mice on HS diet. Conclusions: These data suggest that HS-induced PPARα-mediated downregulation of PHD1 is a novel pathway for PHD/HIF-1α transcriptional regulation for adaptive responses to promote renal function via downstream signaling involving NOS and HO.

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Competitive HIF Prolyl Hydroxylase Inhibitors Show Protection against Oxidative Stress by a Mechanism Partially Dependent on Glycolysis

ISRN Neuroscience ◽

10.1155/2013/598587 ◽

2013 ◽

Vol 2013 ◽

pp. 1-11 ◽

Cited By ~ 3

Author(s):

Ann-Louise Bergström ◽

Karina Fog ◽

Thomas Nikolaj Sager ◽

Anne Techau Bruun ◽

Kenneth Thirstrup

Keyword(s):

Oxidative Stress ◽

Hypoxia Inducible Factor ◽

Large Degree ◽

Cell Types ◽

Prolyl Hydroxylase ◽

Adaptation To Hypoxia ◽

Cellular Effects ◽

Competitive Inhibitors ◽

Inhibitor Compounds ◽

Hif Prolyl Hydroxylase

The hypoxia inducible factor 1 (HIF-1) is a central transcription factor involved in the cellular and molecular adaptation to hypoxia and low glucose supply. The level of HIF-1 is to a large degree regulated by the HIF prolyl hydroxylase enzymes (HPHs) belonging to the Fe(II) and 2-oxoglutarate-dependent dioxygenase superfamily. In the present study, we compared competitive and noncompetitive HPH-inhibitor compounds in two different cell types (SH-SY5Y and PC12). Although the competitive HPH-inhibitor compounds were found to be pharmacologically more potent than the non-competitive compounds at inhibiting HPH2 and HPH1, this was not translated into the cellular effects of the compounds, where the non-competitive inhibitors were actually more potent than the competitive in stabilizing and translocatingHIF1αto the nucleus (quantified with Cellomics ArrayScan technology). This could be explained by the high cellular concentrations of the cofactor 2-oxoglutarate (2-OG) as the competitive inhibitors act by binding to the 2-OG site of the HPH enzymes. Both competitive and non-competitive HPH inhibitors protected the cells against 6-OHDA induced oxidative stress. In addition, the protective effect of a specific HPH inhibitor was partially preserved when the cells were serum starved and exposed to 2-deoxyglucose, an inhibitor of glycolysis, indicating that other processes than restoring energy supply could be important for the HIF-mediated cytoprotection.

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Renal Overexpression of Atrial Natriuretic Peptide and Hypoxia Inducible Factor-1αas Adaptive Response to a High Salt Diet

BioMed Research International ◽

10.1155/2014/936978 ◽

2014 ◽

Vol 2014 ◽

pp. 1-10 ◽

Cited By ~ 1

Author(s):

Silvana Lorena Della Penna ◽

Gabriel Cao ◽

Andrea Carranza ◽

Elsa Zotta ◽

Susana Gorzalczany ◽

...

Keyword(s):

Oxidative Stress ◽

Atrial Natriuretic Peptide ◽

Natriuretic Peptide ◽

Adaptive Response ◽

Hypoxia Inducible Factor ◽

High Salt ◽

High Salt Diet ◽

Salt Diet ◽

Sodium Overload ◽

Atrial Natriuretic

In the kidney, a high salt intake favors oxidative stress and hypoxia and causes the development of fibrosis. Both atrial natriuretic peptide (ANP) and hypoxia inducible factor (HIF-1α) exert cytoprotective effects. We tested the hypothesis that renal expression of ANP and HIF-1αis involved in a mechanism responding to the oxidative stress produced in the kidneys of rats chronically fed a high sodium diet. Sprague-Dawley rats were fed with a normal salt (0.4% NaCl) (NS) or a high salt (8% NaCl) (HS) diet for 3 weeks, with or without the administration of tempol (T), an inhibitor of oxidative stress, in the drinking water. We measured the mean arterial pressure (MAP), glomerular filtration rate (GFR), and urinary sodium excretion (UVNa). We evaluated the expression of ANP, HIF-1α, and transforming growth factor (TGF-β1) in renal tissues by western blot and immunohistochemistry. The animals fed a high salt diet showed increased MAP andUVNalevels and enhanced renal immunostaining of ANP, HIF-1α, and TGF-β1. The administration of tempol together with the sodium overload increased the natriuresis further and prevented the elevation of blood pressure and the increased expression of ANP, TGF-β1, and HIF-1αcompared to their control. These findings suggest that HIF-1αand ANP, synthesized by the kidney, are involved in an adaptive mechanism in response to a sodium overload to prevent or attenuate the deleterious effects of the oxidative stress and the hypoxia on the development of fibrosis.Erratum to “Renal Overexpression of Atrial Natriuretic Peptide and Hypoxia Inducible Factor-1α as Adaptive Response to a High Salt Diet”

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Hypoxia-inducible factor prolyl hydroxylase domain (PHD) inhibition after contusive spinal cord injury does not improve locomotor recovery

PLoS ONE ◽

10.1371/journal.pone.0249591 ◽

2021 ◽

Vol 16 (4) ◽

pp. e0249591

Author(s):

George Z. Wei ◽

Sujata Saraswat Ohri ◽

Nicolas K. Khattar ◽

Adam W. Listerman ◽

Catherine H. Doyle ◽

...

Keyword(s):

Oxidative Stress ◽

Spinal Cord ◽

Spinal Cord Injury ◽

White Matter ◽

Hypoxia Inducible Factor ◽

Prolyl Hydroxylase ◽

Locomotor Recovery ◽

Genetic Ablation ◽

Cord Injury ◽

Prolyl Hydroxylase Domain

Traumatic spinal cord injury (SCI) is a devastating neurological condition that involves both primary and secondary tissue loss. Various cytotoxic events including hypoxia, hemorrhage and blood lysis, bioenergetic failure, oxidative stress, endoplasmic reticulum (ER) stress, and neuroinflammation contribute to secondary injury. The HIF prolyl hydroxylase domain (PHD/EGLN) family of proteins are iron-dependent, oxygen-sensing enzymes that regulate the stability of hypoxia inducible factor-1α (HIF-1α) and also mediate oxidative stress caused by free iron liberated from the lysis of blood. PHD inhibition improves outcome after experimental intracerebral hemorrhage (ICH) by reducing activating transcription factor 4 (ATF4)-driven neuronal death. As the ATF4-CHOP (CCAAT-enhancer-binding protein homologous protein) pathway plays a role in the pathogenesis of contusive SCI, we examined the effects of PHD inhibition in a mouse model of moderate T9 contusive SCI in which white matter damage is the primary driver of locomotor dysfunction. Pharmacological inhibition of PHDs using adaptaquin (AQ) moderately lowers acute induction of Atf4 and Chop mRNAs and prevents the acute decline of oligodendrocyte (OL) lineage mRNAs, but does not improve long-term recovery of hindlimb locomotion or increase chronic white matter sparing. Conditional genetic ablation of all three PHD isoenzymes in OLs did not affect Atf4, Chop or OL mRNAs expression levels, locomotor recovery, and white matter sparing after SCI. Hence, PHDs may not be suitable targets to improve outcomes in traumatic CNS pathologies that involve acute white matter injury.

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POS-285 EXPANDING THE POTENTIAL BENEFIT OF HYPOXIA-INDUCIBLE FACTOR PROLYL HYDROXYLASE INHIBITORS FOR IMPROVING DYSLIPIDEMIA IN ANEMIA OF CHRONIC KIDNEY DISEASE PATIENTS: META-ANALYSIS OF RANDOMIZED CONTROLLED TRIALS

Kidney International Reports ◽

10.1016/j.ekir.2021.03.300 ◽

2021 ◽

Vol 6 (4) ◽

pp. S121-S122

Author(s):

B.P. PUTRA ◽

F.N. Putra

Keyword(s):

Chronic Kidney Disease ◽

Kidney Disease ◽

Randomized Controlled Trials ◽

Potential Benefit ◽

Meta Analysis ◽

Hypoxia Inducible Factor ◽

Prolyl Hydroxylase ◽

Controlled Trials ◽

Randomized Controlled

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Minocycline accelerates hypoxia-inducible factor-1 alpha degradation and inhibits hypoxia-induced neovasculogenesis through prolyl hydroxylase, von Hippel–Lindau-dependent pathway

Archives of Toxicology ◽

10.1007/s00204-013-1175-5 ◽

2013 ◽

Cited By ~ 1

Author(s):

Ching-Hao Li ◽

Po-Lin Liao ◽

Ya-Ting Yang ◽

Shih-Hsuan Huang ◽

Cheng-Hui Lin ◽

...

Keyword(s):

Hypoxia Inducible Factor ◽

Prolyl Hydroxylase ◽

Von Hippel Lindau ◽

Hypoxia Inducible Factor 1 ◽

Dependent Pathway

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Enhancement of Angiogenesis Through Stabilization of Hypoxia-inducible Factor-1 by Silencing Prolyl Hydroxylase Domain-2 Gene

Molecular Therapy ◽

10.1038/mt.2008.90 ◽

2008 ◽

Vol 16 (7) ◽

pp. 1227-1234 ◽

Cited By ~ 28

Author(s):

Shourong Wu ◽

Nobuhiro Nishiyama ◽

Mitsunobu R Kano ◽

Yasuyuki Morishita ◽

Kohei Miyazono ◽

...

Keyword(s):

Hypoxia Inducible Factor ◽

Prolyl Hydroxylase ◽

Hypoxia Inducible Factor 1 ◽

Prolyl Hydroxylase Domain

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A Novel Hypoxia-Inducible Factor−Prolyl Hydroxylase Inhibitor (GSK1278863) for Anemia in CKD: A 28-Day, Phase 2A Randomized Trial

American Journal of Kidney Diseases ◽

10.1053/j.ajkd.2015.11.021 ◽

2016 ◽

Vol 67 (6) ◽

pp. 861-871 ◽

Cited By ~ 79

Author(s):

Richard A. Brigandi ◽

Brendan Johnson ◽

Coreen Oei ◽

Mark Westerman ◽

Gordana Olbina ◽

...

Keyword(s):

Randomized Trial ◽

Hypoxia Inducible Factor ◽

Prolyl Hydroxylase ◽

Prolyl Hydroxylase Inhibitor

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Biochemical characterization of human HIF hydroxylases using HIF protein substrates that contain all three hydroxylation sites

Biochemical Journal ◽

10.1042/bj20101201 ◽

2011 ◽

Vol 436 (2) ◽

pp. 363-369 ◽

Cited By ~ 25

Author(s):

Melissa B. Pappalardi ◽

Dean E. McNulty ◽

John D. Martin ◽

Kelly E. Fisher ◽

Yong Jiang ◽

...

Keyword(s):

Biochemical Characterization ◽

Hypoxia Inducible Factor ◽

Prolyl Hydroxylase ◽

Transactivation Domain ◽

Prolyl Hydroxylases ◽

Proline Residue ◽

Protein Substrates ◽

Steady State Kinetic ◽

Asparaginyl Hydroxylase

The HIF (hypoxia-inducible factor) plays a central regulatory role in oxygen homoeostasis. HIF proteins are regulated by three Fe(II)- and α-KG (α-ketoglutarate)-dependent prolyl hydroxylase enzymes [PHD (prolyl hydroxylase domain) isoenzymes 1–3 or PHD1, PHD2 and PHD3] and one asparaginyl hydroxylase [FIH (factor inhibiting HIF)]. The prolyl hydroxylases control the abundance of HIF through oxygen-dependent hydroxylation of specific proline residues in HIF proteins, triggering subsequent ubiquitination and proteasomal degradation. FIH inhibits the HIF transcription activation through asparagine hydroxylation. Understanding the precise roles and regulation of these four Fe(II)- and α-KG-dependent hydroxylases is of great importance. In the present paper, we report the biochemical characterization of the first HIF protein substrates that contain the CODDD (C-terminal oxygen-dependent degradation domain), the NODDD (N-terminal oxygen-dependent degradation domain) and the CAD (C-terminal transactivation domain). Using LC-MS/MS (liquid chromatography–tandem MS) detection, we show that all three PHD isoenzymes have a strong preference for hydroxylation of the CODDD proline residue over the NODDD proline residue and the preference is observed for both HIF1α and HIF2α protein substrates. In addition, steady-state kinetic analyses show differential substrate selectivity for HIF and α-KG in reference to the three PHD isoforms and FIH.

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