Regulation of hypoxia inducible factor/prolyl hydroxylase binding domain proteins 1 by PPARα and high salt diet

2018 ◽  
Vol 29 (2) ◽  
pp. 165-173 ◽  
Author(s):  
Ezinne Ozurumba ◽  
Omana Mathew ◽  
Katsuri Ranganna ◽  
Myung Choi ◽  
Adebayo Oyekan
Keyword(s):  
Renal Function ◽  
Heme Oxygenase ◽  
Adaptive Response ◽  
Hypoxia Inducible Factor ◽  
Prolyl Hydroxylase ◽  
High Salt ◽  
Kidney Cortex ◽  
Acid Oxidation ◽  
Peroxisome Proliferator ◽  
Knock Out

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.

scholarly journals Metabolic Syndrome and Salt-Sensitive Hypertension in Polygenic Obese TALLYHO/JngJ Mice: Role of Na/K-ATPase Signaling

2019 ◽  
Vol 20 (14) ◽  
pp. 3495 ◽  
Author(s):  
Yanling Yan ◽  
Jiayan Wang ◽  
Muhammad A. Chaudhry ◽  
Ying Nie ◽  
Shuyan Sun ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Renal Function ◽  
Significant Rise ◽  
Protein Carbonylation ◽  
High Salt ◽  
Kidney Cortex ◽  
High Salt Diet ◽  
Salt Diet ◽  
Salt Sensitive Hypertension

We have demonstrated that Na/K-ATPase acts as a receptor for reactive oxygen species (ROS), regulating renal Na+ handling and blood pressure. TALLYHO/JngJ (TH) mice are believed to mimic the state of obesity in humans with a polygenic background of type 2 diabetes. This present work is to investigate the role of Na/K-ATPase signaling in TH mice, focusing on susceptibility to hypertension due to chronic excess salt ingestion. Age-matched male TH and the control C57BL/6J (B6) mice were fed either normal diet or high salt diet (HS: 2, 4, and 8% NaCl) to construct the renal function curve. Na/K-ATPase signaling including c-Src and ERK1/2 phosphorylation, as well as protein carbonylation (a commonly used marker for enhanced ROS production), were assessed in the kidney cortex tissues by Western blot. Urinary and plasma Na+ levels were measured by flame photometry. When compared to B6 mice, TH mice developed salt-sensitive hypertension and responded to a high salt diet with a significant rise in systolic blood pressure indicative of a blunted pressure-natriuresis relationship. These findings were evidenced by a decrease in total and fractional Na+ excretion and a right-shifted renal function curve with a reduced slope. This salt-sensitive hypertension correlated with changes in the Na/K-ATPase signaling. Specifically, Na/K-ATPase signaling was not able to be stimulated by HS due to the activated baseline protein carbonylation, phosphorylation of c-Src and ERK1/2. These findings support the emerging view that Na/K-ATPase signaling contributes to metabolic disease and suggest that malfunction of the Na/K-ATPase signaling may promote the development of salt-sensitive hypertension in obesity. The increased basal level of renal Na/K-ATPase-dependent redox signaling may be responsible for the development of salt-sensitive hypertension in polygenic obese TH mice.

scholarly journals SIRT3 deficiency exacerbates fatty liver by attenuating the HIF1α-LIPIN 1 pathway and increasing CD36 through Nrf2

2020 ◽  
Vol 18 (1) ◽  
Author(s):  
Emma Barroso ◽  
Rosalía Rodríguez-Rodríguez ◽  
Mohammad Zarei ◽  
Javier Pizarro-Degado ◽  
Anna Planavila ◽  
...  
Keyword(s):  
Hepatic Steatosis ◽  
Target Genes ◽  
Hypoxia Inducible Factor ◽  
Redox Status ◽  
Acid Oxidation ◽  
Standard Diet ◽  
Peroxisome Proliferator ◽  
Lipid Uptake ◽  
Peroxisome Proliferator Activated Receptor ◽  
Vldl Receptor

Abstract Background Deficiency of mitochondrial sirtuin 3 (SIRT3), a NAD+-dependent protein deacetylase that maintains redox status and lipid homeostasis, contributes to hepatic steatosis. In this study, we investigated additional mechanisms that might play a role in aggravating hepatic steatosis in Sirt3-deficient mice fed a high-fat diet (HFD). Methods Studies were conducted in wild-type (WT) and Sirt3−/− mice fed a standard diet or a HFD and in SIRT3-knockdown human Huh-7 hepatoma cells. Results Sirt3−/− mice fed a HFD presented exacerbated hepatic steatosis that was accompanied by decreased expression and DNA-binding activity of peroxisome proliferator-activated receptor (PPAR) α and of several of its target genes involved in fatty acid oxidation, compared to WT mice fed the HFD. Interestingly, Sirt3 deficiency in liver and its knockdown in Huh-7 cells resulted in upregulation of the nuclear levels of LIPIN1, a PPARα co-activator, and of the protein that controls its levels and localization, hypoxia-inducible factor 1α (HIF-1α). These changes were prevented by lipid exposure through a mechanism that might involve a decrease in succinate levels. Finally, Sirt3−/− mice fed the HFD showed increased levels of some proteins involved in lipid uptake, such as CD36 and the VLDL receptor. The upregulation in CD36 was confirmed in Huh-7 cells treated with a SIRT3 inhibitor or transfected with SIRT3 siRNA and incubated with palmitate, an effect that was prevented by the Nrf2 inhibitor ML385. Conclusion These findings demonstrate new mechanisms by which Sirt3 deficiency contributes to hepatic steatosis. Graphical abstract

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

2014 ◽  
Vol 2014 ◽  
pp. 1-10 ◽  
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”

scholarly journals Leptin decreases BC cell susceptibility to NK lysis via PGC1A pathway

2020 ◽  
Vol 9 (6) ◽  
pp. 578-586
Author(s):  
Hichem Bouguerra ◽  
Gorrab Amal ◽  
Stephan Clavel ◽  
Hamouda Boussen ◽  
Jean-François Louet ◽  
...  
Keyword(s):  
Mrna Level ◽  
Hypoxia Inducible Factor ◽  
Tumor Development ◽  
Underlying Mechanism ◽  
Acid Oxidation ◽  
Peroxisome Proliferator ◽  
Tumor Escape ◽  
Tumor Resistance ◽  
Peroxisome Proliferator Activated Receptor ◽  
Potential Implication

Large prospective studies established a link between obesity and breast cancer (BC) development. Yet, the mechanisms underlying this association are not fully understood. Among the diverse adipocytokine secreted by hypertrophic adipose tissue, leptin is emerging as a key candidate molecule linking obesity and cancer, since it promotes proliferation and invasiveness of tumors. However, the potential implication of leptin on tumor escape mechanisms remains unknown. This study aims to explore the effect of leptin on tumor resistance to NK lysis and the underlying mechanism. We found that leptin promotes both BC resistance to NK92-mediated lysis and β oxidation on MCF-7, by the up-regulation of a master regulator of mitochondrial biogenesis, the peroxisome proliferator activated receptor coactivator-1 α (PGC1A). Using adenoviral approaches, we show that acute elevation of PGC1A enhances the fatty acid oxidation pathway and decreases the susceptibility of BC cells to NK92-mediated lysis. Importantly, we identified the involvement of PGC1A and leptin in the regulation of hypoxia inducible factor-1 alpha (HIF1A) expression by tumor cells. We further demonstrate that basal BC cells MDA-MB-231 and BT-20 exhibit an increased PGC1A mRNA level and an enhanced oxidative phosphorylation activity; in comparison with luminal BC cells MCF7 and MDA-361, which are associated with more resistance NK92 lysis. Altogether, our results demonstrate for the first time how leptin could promote tumor resistance to immune attacks. Reagents blocking leptin or PGC1A activity might aid in developing new therapeutic strategies to limit tumor development in obese BC patients.

scholarly journals Impact of Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitor on Renal Function in Patient with Heart Failure

2021 ◽  
Vol 8 (12) ◽  
pp. 189
Author(s):  
Teruhiko Imamura ◽  
Yohei Ueno ◽  
Koichiro Kinugawa
Keyword(s):  
Heart Failure ◽  
Renal Function ◽  
Large Scale ◽  
Hypoxia Inducible Factor ◽  
Prolyl Hydroxylase ◽  
Renal Anemia ◽  
Oral Agent ◽  
Therapeutic Tool ◽  
Reduced Ejection Fraction ◽  
Patients With Heart Failure

Hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitor is a recently introduced oral agent to treat renal anemia, but its clinical implications on renal functioning in patients with heart failure remains unknown. We studied an 81-year-old man with heart failure with mildly reduced ejection fraction, chronic kidney disease, and renal anemia. The seven-month HIF-PH inhibitor daprodustat treatment improved the hemoglobin level from 7.4 g/dL to 11.8 g/dL and estimated glomerular filtration ratio from 24 mL/min/1.73 m2 to 35 mL/min/1.73 m2 without any complications, including thromboembolic events. HIF-PH inhibitor might be a promising therapeutic tool to improve renal anemia and renal function in patients with heart failure, although large-scale studies are warranted to validate our findings.

Natural Aldose Reductase Inhibitor: A Potential Therapeutic Agent for Non-alcoholic Fatty Liver Disease

2020 ◽  
Vol 21 (6) ◽  
pp. 599-609 ◽  
Author(s):  
Longxin Qiu ◽  
Chang Guo
Keyword(s):  
Oxidative Stress ◽  
Liver Disease ◽  
Fatty Liver ◽  
Aldose Reductase ◽  
Fatty Liver Disease ◽  
Acid Oxidation ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Alcoholic Fatty Liver ◽  
Nonalcoholic Fatty Liver

Aldose reductase (AR) has been reported to be involved in the development of nonalcoholic fatty liver disease (NAFLD). Hepatic AR is induced under hyperglycemia condition and converts excess glucose to lipogenic fructose, which contributes in part to the accumulation of fat in the liver cells of diabetes rodents. In addition, the hyperglycemia-induced AR or nutrition-induced AR causes suppression of the transcriptional activity of peroxisome proliferator-activated receptor (PPAR) α and reduced lipolysis in the liver, which also contribute to the development of NAFLD. Moreover, AR induction in non-alcoholic steatohepatitis (NASH) may aggravate oxidative stress and the expression of inflammatory cytokines in the liver. Here, we summarize the knowledge on AR inhibitors of plant origin and review the effect of some plant-derived AR inhibitors on NAFLD/NASH in rodents. Natural AR inhibitors may improve NAFLD at least in part through attenuating oxidative stress and inflammatory cytokine expression. Some of the natural AR inhibitors have been reported to attenuate hepatic steatosis through the regulation of PPARα-mediated fatty acid oxidation. In this review, we propose that the natural AR inhibitors are potential therapeutic agents for NAFLD.

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