scholarly journals A Pharmacologic “Stress Test” for Assessing Select Antioxidant Defenses in Patients with CKD

2020 ◽  
Vol 15 (5) ◽  
pp. 633-642 ◽  
Author(s):  
Richard A. Zager ◽  
Ali C.M. Johnson ◽  
Alvaro Guillem ◽  
Jeff Keyser ◽  
Bhupinder Singh
Keyword(s):  
Kidney Disease ◽  
Healthy Volunteers ◽  
Stress Test ◽  
Oxidant Stress ◽  
Pharmacologic Stress ◽  
Antioxidant Defenses ◽  
Heme Oxygenase 1 ◽  
High Dose ◽  
Clinical Trial Registry ◽  
Antioxidant Proteins

Background and objectivesOxidative stress is a hallmark and mediator of CKD. Diminished antioxidant defenses are thought to be partly responsible. However, there is currently no way to prospectively assess antioxidant defenses in humans. Tin protoporphyrin (SnPP) induces mild, transient oxidant stress in mice, triggering increased expression of select antioxidant proteins (e.g., heme oxygenase 1 [HO-1], NAD[P]H dehydrogenase [quinone] 1 [NQO1], ferritin, p21). Hence, we tested the hypothesis that SnPP can also variably increase these proteins in humans and can thus serve as a pharmacologic “stress test” for gauging gene responsiveness and antioxidant reserves.Design, setting, participants, & measurementsA total of 18 healthy volunteers and 24 participants with stage 3 CKD (n=12; eGFR 30–59 ml/min per 1.73 m2) or stage 4 CKD (n=12; eGFR 15–29 ml/min per 1.73 m2) were injected once with SnPP (9, 27, or 90 mg). Plasma and/or urinary antioxidant proteins were measured at baseline and for up to 4 days post-SnPP dosing. Kidney safety was gauged by serial measurements of BUN, creatinine, eGFR, albuminuria, and four urinary AKI biomarkers (kidney injury molecule 1, neutrophil gelatinase-associated lipocalin, cystatin C, and N-acetyl glucosaminidase).ResultsPlasma HO-1, ferritin, p21, and NQO1 were all elevated at baseline in CKD participants. Plasma HO-1 and urine NQO1 levels each inversely correlated with eGFR (r=−0.85 to −0.95). All four proteins manifested statistically significant dose- and time-dependent elevations after SnPP injection. However, marked intersubject differences were observed. p21 responses to high-dose SnPP and HO-1 responses to low-dose SnPP were significantly suppressed in participants with CKD versus healthy volunteers. SnPP was well tolerated by all participants, and no evidence of nephrotoxicity was observed.ConclusionsSnPP can be safely administered and, after its injection, the resulting changes in plasma HO-1, NQO1, ferritin, and p21 concentrations can provide information as to antioxidant gene responsiveness/reserves in subjects with and without kidney disease.Clinical Trial registry name and registration numberA Study with RBT-1, in Healthy Volunteers and Subjects with Stage 3–4 Chronic Kidney Disease, NCT0363002 and NCT03893799

scholarly journals The NRF2 knockout rat: a new animal model to study endothelial dysfunction, oxidant stress, and microvascular rarefaction

2016 ◽  
Vol 310 (4) ◽  
pp. H478-H487 ◽  
Author(s):  
Jessica R. C. Priestley ◽  
Katie E. Kautenburg ◽  
Marc C. Casati ◽  
Bradley T. Endres ◽  
Aron M. Geurts ◽  
...  
Keyword(s):  
Superoxide Dismutase ◽  
Endothelial Dysfunction ◽  
Oxidant Stress ◽  
Antioxidant Defenses ◽  
Start Codon ◽  
Heme Oxygenase 1 ◽  
Ang Ii ◽  
Wild Type ◽  
Transcription Activator ◽  
Therapeutic Benefits

Nuclear factor (erythroid-derived 2)-like-2 (NRF2) is a master antioxidant and cell protective transcription factor that upregulates antioxidant defenses. In this study we developed a strain of Nrf2 null mutant rats to evaluate the role of reduced NRF2-regulated antioxidant defenses in contributing to endothelial dysfunction and impaired angiogenic responses during salt-induced ANG II suppression. Nrf2−/− mutant rats were developed using transcription activator-like effector nuclease technology in the Sprague-Dawley genetic background, and exhibited a 41-bp deletion that included the start codon for Nrf2 and an absence of immunohistochemically detectable NRF2 protein. Expression of mRNA for the NRF2-regulated indicator enzymes heme oxygenase-1, catalase, superoxide dismutase 1, superoxide dismutase 2, and glutathione reductase was significantly lower in livers of Nrf2−/− mutant rats fed high salt (HS; 4% NaCl) for 2 wk compared with wild-type controls. Endothelium-dependent dilation to acetylcholine was similar in isolated middle cerebral arteries (MCA) of Nrf2−/− mutant rats and wild-type littermates fed low-salt (0.4% NaCl) diet, and was eliminated by short-term (3 days) HS diet in both strains. Low-dose ANG II infusion (100 ng/kg sc) reversed salt-induced endothelial dysfunction in MCA and prevented microvessel rarefaction in wild-type rats fed HS diet, but not in Nrf2−/− mutant rats. The results of this study indicate that suppression of NRF2 antioxidant defenses plays an essential role in the development of salt-induced oxidant stress, endothelial dysfunction, and microvessel rarefaction in normotensive rats and emphasize the potential therapeutic benefits of directly upregulating NRF2-mediated antioxidant defenses to ameliorate vascular oxidant stress in humans.

Involvement of Heme Oxygenase-1 in Neuropsychiatric and Neurodegenerative Diseases

2018 ◽  
Vol 24 (20) ◽  
pp. 2283-2302 ◽  
Author(s):  
Vivian B. Neis ◽  
Priscila B. Rosa ◽  
Morgana Moretti ◽  
Ana Lucia S. Rodrigues
Keyword(s):  
Neurodegenerative Diseases ◽  
Heme Oxygenase ◽  
Therapeutic Potential ◽  
Redox Homeostasis ◽  
Antioxidant Defenses ◽  
Heme Oxygenase 1 ◽  
Physiological Conditions ◽  
And Oxidative Stress ◽  
Defensive Mechanism

Heme oxygenase (HO) family catalyzes the conversion of heme into free iron, carbon monoxide and biliverdin. It possesses two well-characterized isoforms: HO-1 and HO-2. Under brain physiological conditions, the expression of HO-2 is constitutive, abundant and ubiquitous, whereas HO-1 mRNA and protein are restricted to small populations of neurons and neuroglia. HO-1 is an inducible enzyme that has been shown to participate as an essential defensive mechanism for neurons exposed to oxidant challenges, being related to antioxidant defenses in certain neuropathological conditions. Considering that neurodegenerative diseases (Alzheimer’s Disease (AD), Parkinson’s Disease (PD) and Multiple Sclerosis (MS)) and neuropsychiatric disorders (depression, anxiety, Bipolar Disorder (BD) and schizophrenia) are associated with increased inflammatory markers, impaired redox homeostasis and oxidative stress, conditions that may be associated with alterations in HO-levels/activity, the purpose of this review is to present evidence on the possible role of HO-1 in these Central Nervous System (CNS) diseases. In addition, the possible therapeutic potential of targeting brain HO-1 is explored in this review.

scholarly journals Mitigation of Aflatoxin B1 Hepatoxicity by Dietary Hedyotis diffusa Is Associated with Activation of NRF2/ARE Signaling in Chicks

Antioxidants ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 878
Author(s):  
Ling Zhao ◽  
Jiang Deng ◽  
Zi-Jian Xu ◽  
Wan-Po Zhang ◽  
Mahmoud Mohamed Khalil ◽  
...  
Keyword(s):  
Aflatoxin B1 ◽  
Body Weight Gain ◽  
Control Diet ◽  
Protein Carbonyl ◽  
Heme Oxygenase 1 ◽  
High Dose ◽  
Feed Conversion ◽  
Quinone Oxidoreductase ◽  
Vacuolar Degeneration ◽  
Hedyotis Diffusa

The objective of this study was to explore the mechanism of Hedyotis diffusa (HD) in mediating the detoxification of aflatoxin B1 (AFB1)-induced hepatic injury in chicks. A total of 144 one-day-old male broilers (Cobb 500) were randomly assigned to four treatment groups (n = 6 cages/diet, 6 chicks/cage). After three days of acclimation, the broilers were fed either a control diet (Control), Control plus 0.5 mg/kg of AFB1, or Control plus 0.5 mg/kg AFB1 with 500 or 1000 mg/kg HD for two weeks. Both serum and liver were collected at the end of the feeding trial for biochemistry, histology, and NF-E2-related nuclear factor 2 (NRF2)/antioxidant response element (ARE) signaling analysis. Compared with Control, the AFB1 treatment caused liver injury and decreased (p < 0.05) body weight gain, feed intake, feed conversion ratio, and serum albumin and total protein by 6.2–20.7%. AFB1 also induced swelling, necrosis, and severe vacuolar degeneration in chicks’ livers. Notably, HD supplementation at 500 and 1000 mg/kg mitigated (p < 0.05) the alterations induced by AFB1. HD supplementation alleviated (p < 0.05) AFB1-induced impairment in hepatic glutathione peroxidase activity, protein carbonyl, and exo-AFB1-8,9-epoxide (AFBO)–DNA concentrations by 57.7–100% and increased (p < 0.05) the activities of superoxide dismutase and catalase by 23.1–40.9% more than those of AFB1 treatment alone. Furthermore, HD supplementation at the two doses upregulated (p < 0.05) NRF2, NAD(P)H: quinone oxidoreductase-1, heme oxygenase-1, glutathione cysteine ligase catalytic subunit, and glutathione-S transferase A2 and A3 in livers relative to the AFB1 group by 0.99–3.4-fold. Overall, dietary supplementation of HD at a high dose displayed better protection effects against aflatoxicosis. In conclusion, a dietary HD supplementation at 500 and 1000 mg/kg protected broilers from AFB1-induced hepatotoxicity, potentially due to the activation of NRF2/ARE signaling in the chicks.

scholarly journals Uremic Toxins and Frailty in Patients with Chronic Kidney Disease: A Molecular Insight

2021 ◽  
Vol 22 (12) ◽  
pp. 6270
Author(s):  
Chia-Ter Chao ◽  
Shih-Hua Lin
Keyword(s):  
Chronic Kidney Disease ◽  
Renal Function ◽  
Kidney Disease ◽  
Uremic Toxins ◽  
Heme Oxygenase 1 ◽  
Signal Pathways ◽  
Uremic Toxin ◽  
Nuclear Factor ◽  
Cognitive Frailty ◽  
Renal Function Decline

The accumulation of uremic toxins (UTs) is a prototypical manifestation of uremic milieu that follows renal function decline (chronic kidney disease, CKD). Frailty as a potential outcome-relevant indicator is also prevalent in CKD. The intertwined relationship between uremic toxins, including small/large solutes (phosphate, asymmetric dimethylarginine) and protein-bound ones like indoxyl sulfate (IS) and p-cresyl sulfate (pCS), and frailty pathogenesis has been documented recently. Uremic toxins were shown in vitro and in vivo to induce noxious effects on many organ systems and likely influenced frailty development through their effects on multiple preceding events and companions of frailty, such as sarcopenia/muscle wasting, cognitive impairment/cognitive frailty, osteoporosis/osteodystrophy, vascular calcification, and cardiopulmonary deconditioning. These organ-specific effects may be mediated through different molecular mechanisms or signal pathways such as peroxisome proliferator-activated receptor γ coactivator 1-α (PGC-1α), mitogen-activated protein kinase (MAPK) signaling, aryl hydrocarbon receptor (AhR)/nuclear factor-κB (NF-κB), nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), Runt-related transcription factor 2 (RUNX2), bone morphogenic protein 2 (BMP2), osterix, Notch signaling, autophagy effectors, microRNAs, and reactive oxygen species induction. Anecdotal clinical studies also suggest that frailty may further accelerate renal function decline, thereby augmenting the accumulation of UTs in affected individuals. Judging from these threads of evidence, management strategies aiming for uremic toxin reduction may be a promising approach for frailty amelioration in patients with CKD. Uremic toxin lowering strategies may bear the potential of improving patients’ outcomes and restoring their quality of life, through frailty attenuation. Pathogenic molecule-targeted therapeutics potentially disconnect the association between uremic toxins and frailty, additionally serving as an outcome-modifying approach in the future.

scholarly journals Heme Oxygenase 1: A Defensive Mediator in Kidney Diseases

2021 ◽  
Vol 22 (4) ◽  
pp. 2009
Author(s):  
Anne Grunenwald ◽  
Lubka T. Roumenina ◽  
Marie Frimat
Keyword(s):  
Kidney Disease ◽  
Heme Oxygenase ◽  
Current Knowledge ◽  
Kidney Diseases ◽  
Heme Oxygenase 1 ◽  
Wide Range ◽  
Significant Burden ◽  
Stage Renal Disease ◽  
End Stage ◽  
Positive Effect

The incidence of kidney disease is rising, constituting a significant burden on the healthcare system and making identification of new therapeutic targets increasingly urgent. The heme oxygenase (HO) system performs an important function in the regulation of oxidative stress and inflammation and, via these mechanisms, is thought to play a role in the prevention of non-specific injuries following acute renal failure or resulting from chronic kidney disease. The expression of HO-1 is strongly inducible by a wide range of stimuli in the kidney, consequent to the kidney’s filtration role which means HO-1 is exposed to a wide range of endogenous and exogenous molecules, and it has been shown to be protective in a variety of nephropathological animal models. Interestingly, the positive effect of HO-1 occurs in both hemolysis- and rhabdomyolysis-dominated diseases, where the kidney is extensively exposed to heme (a major HO-1 inducer), as well as in non-heme-dependent diseases such as hypertension, diabetic nephropathy or progression to end-stage renal disease. This highlights the complexity of HO-1’s functions, which is also illustrated by the fact that, despite the abundance of preclinical data, no drug targeting HO-1 has so far been translated into clinical use. The objective of this review is to assess current knowledge relating HO-1’s role in the kidney and its potential interest as a nephroprotection agent. The potential therapeutic openings will be presented, in particular through the identification of clinical trials targeting this enzyme or its products.

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