Pre-clinical model of severe glutathione peroxidase-3 deficiency and chronic kidney disease results in coronary artery thrombosis and depressed left ventricular function

Pang, Paul; Abbott, Molly; Abdi, Malyun; Fucci, Quynh-Anh; Chauhan, Nikita; Mistri, Murti; Proctor, Brandon M.; Chin, Michael C.; Wang, Bin; Yin, Wenqing; Lu, Tzongshi; Halim, Arvin; Lim, Kenneth; Handy, Diane E.; Loscalzo, Joseph; Siedlecki, Andrew

doi:10.1093/ndt/gfx304

Cited by 39 publications

(35 citation statements)

References 65 publications

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“…Extreme GPx3 deficiency was also associated with an activation of the myocardial platelet. Thus, GPx3 deficiency was found to be a significant contributor to the development of kidney disease-induced cardiac disease [61]. Besides, it was disclosed that GPx1 increased activity in erythrocytes accompanies decreased plasma GPx3 activity among CKD patients [4,62].…”

Section: Glutathione Peroxidase Gpx Changes In Ckdmentioning

confidence: 99%

Chronic Kidney Disease as Oxidative Stress- and Inflammatory-Mediated Cardiovascular Disease

Podkowińska¹,

2020

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Generating reactive oxygen species (ROS) is necessary for both physiology and pathology. An imbalance between endogenous oxidants and antioxidants causes oxidative stress, contributing to vascular dysfunction. The ROS-induced activation of transcription factors and proinflammatory genes increases inflammation. This phenomenon is of crucial importance in patients with chronic kidney disease (CKD), because atherosclerosis is one of the critical factors of their cardiovascular disease (CVD) and increased mortality. The effect of ROS disrupts the excretory function of each section of the nephron. It prevents the maintenance of intra-systemic homeostasis and leads to the accumulation of metabolic products. Renal regulatory mechanisms, such as tubular glomerular feedback, myogenic reflex in the supplying arteriole, and the renin–angiotensin–aldosterone system, are also affected. It makes it impossible for the kidney to compensate for water–electrolyte and acid–base disturbances, which progress further in the mechanism of positive feedback, leading to a further intensification of oxidative stress. As a result, the progression of CKD is observed, with a spectrum of complications such as malnutrition, calcium phosphate abnormalities, atherosclerosis, and anemia. This review aimed to show the role of oxidative stress and inflammation in renal impairment, with a particular emphasis on its influence on the most common disturbances that accompany CKD.

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Section: Glutathione Peroxidase Gpx Changes In Ckdmentioning

confidence: 99%

Chronic Kidney Disease as Oxidative Stress- and Inflammatory-Mediated Cardiovascular Disease

Podkowińska¹,

2020

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“…However, a noticeable phenotype of GPX3-/-knock-out mice that recapitulates observations in patients with low systemic GPx3 levels is the susceptibility to thrombosis following platelet activation. GPX3-/-mice display decreased bleeding time compared to wild-type mice, and this was mechanistically linked to enhanced oxidative inactivation of nitric oxide (NO) and consequential increases in thrombosis [41,42]. Moreover, when GPX3-/-knock-out mice were exposed to surgery-induced chronic kidney disease (CKD), these mice displayed decreased left ventricular fractional shortening, increased platelet aggregation, and microthrombi in the myocardium [41].…”

Section: Gpx3 Functionmentioning

confidence: 99%

Extracellular Glutathione Peroxidase GPx3 and Its Role in Cancer

Chang

Worley

Phaëton

et al. 2020

Cancers

153

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Mammalian cells possess a multifaceted antioxidant enzyme system, which includes superoxide dismutases, catalase, the peroxiredoxin/thioredoxin and the glutathione peroxidase systems. The dichotomous role of reactive oxygen species and antioxidant enzymes in tumorigenesis and cancer progression complicates the use of small molecule antioxidants, pro-oxidants, and targeting of antioxidant enzymes as therapeutic approaches for cancer treatment. It also highlights the need for additional studies to investigate the role and regulation of these antioxidant enzymes in cancer. The focus of this review is on glutathione peroxidase 3 (GPx3), a selenoprotein, and the only extracellular GPx of a family of oxidoreductases that catalyze the detoxification of hydro- and soluble lipid hydroperoxides by reduced glutathione. In addition to summarizing the biochemical function, regulation, and disease associations of GPx3, we specifically discuss the role and regulation of systemic and tumor cell expressed GPx3 in cancer. From this it is evident that GPx3 has a dichotomous role in different tumor types, acting as both a tumor suppressor and pro-survival protein. Further studies are needed to examine how loss or gain of GPx3 specifically affects oxidant scavenging and redox signaling in the extracellular tumor microenvironment, and how GPx3 might be targeted for therapeutic intervention.

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“…Furthermore, reduced GPx3 expression is a contributing factor to circulatory diseases, and a contributing factor to developing kidney-induced cardiac disease [50]. Expression of SelenoP is regulated by insulin and glucocorticoid levels, with reduced hepatic SelenoP associated with irregular distribution of selenium throughout the body [51].…”

Section: Offspring Selenoproteinsmentioning

confidence: 99%

Analysis of Selenoprotein Expression in Response to Dietary Selenium Deficiency During Pregnancy Indicates Tissue Specific Differential Expression in Mothers and Sex Specific Changes in the Fetus and Offspring

Hofstee

Cuffe

Perkins

2020

IJMS

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The human selenoproteome is comprised of ~25 genes, which incorporate selenium, in the form of selenocysteine, into their structure. Since it is well known that selenium is important to maternal health and foetal development during pregnancy, this study aimed at defining the impact of selenium deficiency on maternal, placental, foetal and offspring selenoprotein gene expression. Female C57BL/6 mice were randomly allocated to control (>190 μg/kg) or low selenium (<50 μg/kg) diets four weeks prior to mating and throughout gestation. At embryonic day (E)18.5, pregnant mice were sacrificed followed by collection of maternal and foetal tissues. A subset of mice littered down, and offspring were monitored from postnatal day (PN) 8, weaned at PN24 and sacrificed at PN180, followed by tissue collection. Following RNA extraction, the expression of 14 selenoproteins was assessed with qPCR in liver, kidneys, muscle and placenta. Selenium deficiency downregulated expression (Ptrt < 0.05) of many selenoproteins in maternal tissues and the placenta. However, foetal selenoprotein expression was upregulated (Ptrt < 0.05) in all tissues, especially the kidneys. This was not reflected at PN180; however, a sexually dimorphic relationship in selenoprotein expression was observed in offspring. This study demonstrates the selenoproteome is sensitive to dietary selenium levels, which may be exacerbated by pregnancy. We concluded that transcriptional regulation of selenoproteins is complex and multifaceted, with expression exhibiting tissue-, age- and sex-specificities.

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Pre-clinical model of severe glutathione peroxidase-3 deficiency and chronic kidney disease results in coronary artery thrombosis and depressed left ventricular function

Abstract: These results suggest GPx3 deficiency is a substantive contributing factor to the development of kidney disease-induced cardiac disease.

Cited by 39 publications

References 65 publications

Chronic Kidney Disease as Oxidative Stress- and Inflammatory-Mediated Cardiovascular Disease

Chronic Kidney Disease as Oxidative Stress- and Inflammatory-Mediated Cardiovascular Disease

Extracellular Glutathione Peroxidase GPx3 and Its Role in Cancer

Analysis of Selenoprotein Expression in Response to Dietary Selenium Deficiency During Pregnancy Indicates Tissue Specific Differential Expression in Mothers and Sex Specific Changes in the Fetus and Offspring

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