Regulation of hypoxia inducible factor/prolyl hydroxylase binding domain proteins 1 by PPARα and high salt diet
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Ezinne Ozurumba
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.
Author contributions: Ezinne Ozurumba conducted most of the studies involving renal function and the assays for nitric oxide. Drs Ranganna, Mathew and Myung did the Western blotting experiments for the expression of PHD1 and HO-1. Dr Adebayo Oyekan conceptualized and designed the study, analyzed the data and wrote the manuscript. All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.
Research funding: This study was supported by the National Institutes of Health, Funder Id: 10.13039/ 100006545, grant HL03674 and G12 MD007605.
Employment or leadership: None declared.
Honorarium: None declared.
Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.
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©2018 Walter de Gruyter GmbH, Berlin/Boston
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Articles in the same Issue
- Frontmatter
- Minireview
- Acorus calamus: a bio-reserve of medicinal values
- Behavior and Neuroprotection
- Electrodermal response to auditory stimuli in relation to menopausal transition period
- Reproduction
- First-line antituberculosis drugs disrupt endocrine balance and induce ovarian and uterine oxidative stress in rats
- Launaea taraxacifolia (Willd.) Amin ex C. Jeffrey inhibits oxidative damage and econucleotidase followed by increased cellular ATP in testicular cells of rats exposed to metropolitan polluted river water
- Cardiovascular Function
- Ameliorative effect of Azadirachta indica on sodium fluoride-induced hypertension through improvement of antioxidant defence system and upregulation of extracellular signal regulated kinase 1/2 signaling
- Regulation of hypoxia inducible factor/prolyl hydroxylase binding domain proteins 1 by PPARα and high salt diet
- Oxidative Stress
- Amla (Emblica officinalis) improves hepatic and renal oxidative stress and the inflammatory response in hypothyroid female wistar rats fed with a high-fat diet
- Metabolism
- Cocos nucifera water improves metabolic functions in offspring of high fat diet fed Wistar rats
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- Phytotherapy
- An isobolographic analysis of the anti-nociceptive effect of geraniin in combination with morphine or diclofenac
- Antidiarrheal and antimicrobial activities of the ethanol extract from the Icacina senegalensis root bark
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