scholarly journals Maternal Tryptophan Supplementation Protects Adult Rat Offspring against Hypertension Programmed by Maternal Chronic Kidney Disease: Implication of Tryptophan-Metabolizing Microbiome and Aryl Hydrocarbon Receptor

2020 ◽  
Vol 21 (12) ◽  
pp. 4552 ◽  
Author(s):  
Chien-Ning Hsu ◽  
I-Chun Lin ◽  
Hong-Ren Yu ◽  
Li-Tung Huang ◽  
Mao-Meng Tiao ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Gut Microbiota ◽  
Aryl Hydrocarbon Receptor ◽  
Female Rats ◽  
Adult Offspring ◽  
Sprague Dawley ◽  
Aryl Hydrocarbon ◽  
Induced Hypertension ◽  
In Pregnancy

Hypertension and chronic kidney disease (CKD) can originate during early-life. Tryptophan metabolites generated by different pathways have both detrimental and beneficial effects. In CKD, uremic toxins from the tryptophan-generating metabolites are endogenous ligands of the aryl hydrocarbon receptor (AHR). The interplay between AHR, nitric oxide (NO), the renin–angiotensin system (RAS), and gut microbiota is involved in the development of hypertension. We examined whether tryptophan supplementation in pregnancy can prevent hypertension and kidney disease programmed by maternal CKD in adult offspring via the aforementioned mechanisms. Sprague–Dawley (SD) female rats received regular chow or chow supplemented with 0.5% adenine for 3 weeks to induce CKD before pregnancy. Pregnant controls or CKD rats received vehicle or tryptophan 200 mg/kg per day via oral gavage during pregnancy. Male offspring were divided into four groups (n = 8/group): control, CKD, tryptophan supplementation (Trp), and CKD plus tryptophan supplementation (CKDTrp). All rats were sacrificed at the age of 12 weeks. We found maternal CKD induced hypertension in adult offspring, which tryptophan supplementation prevented. Maternal CKD-induced hypertension is related to impaired NO bioavailability and non-classical RAS axis. Maternal CKD and tryptophan supplementation differentially shaped distinct gut microbiota profile in adult offspring. The protective effect of tryptophan supplementation against maternal CKD-induced programmed hypertension is relevant to alterations to several tryptophan-metabolizing microbes and AHR signaling pathway. Our findings support interplay among tryptophan-metabolizing microbiome, AHR, NO, and the RAS in hypertension of developmental origins. Furthermore, tryptophan supplementation in pregnancy could be a potential approach to prevent hypertension programmed by maternal CKD.

Aryl Hydrocarbon Receptor and Uremic Toxins from the Gut Microbiota in Chronic Kidney Disease Patients: Is There a Relationship between Them?

Biochemistry ◽  
2019 ◽  
Vol 58 (15) ◽  
pp. 2054-2060 ◽  
Author(s):  
Jessyca Sousa de Brito ◽  
Natália Alvarenga Borges ◽  
Juliana Saraiva dos Anjos ◽  
Lia Sumie Nakao ◽  
Milena Barcza Stockler-Pinto ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Gut Microbiota ◽  
Aryl Hydrocarbon Receptor ◽  
Uremic Toxins ◽  
Aryl Hydrocarbon

scholarly journals Identification of endogenous 1‐aminopyrene as a novel mediator of progressive chronic kidney disease via aryl hydrocarbon receptor activation

2020 ◽  
Vol 177 (15) ◽  
pp. 3415-3435 ◽  
Author(s):  
Hua Miao ◽  
Gang Cao ◽  
Xia‐Qing Wu ◽  
Yuan‐Yuan Chen ◽  
Dan‐Qian Chen ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Aryl Hydrocarbon Receptor ◽  
Receptor Activation ◽  
Aryl Hydrocarbon

scholarly journals A novel 4 S [3H]β-naphthoflavone-binding protein in liver cytosol of female Sprague–Dawley rats treated with aryl hydrocarbon receptor agonists

2000 ◽  
Vol 347 (3) ◽  
pp. 787-795
Author(s):  
Damian BRAUZE ◽  
Danuta MALEJKA-GIGANTI
Keyword(s):  
Aryl Hydrocarbon Receptor ◽  
Rat Liver ◽  
Binding Protein ◽  
Female Rats ◽  
Sprague Dawley ◽  
Methyltransferase Activity ◽  
Liver Cytosol ◽  
Aryl Hydrocarbon ◽  
Sprague Dawley Rats ◽  
S Peak

β-Naphthoflavone (β-NF) is a widely used inducer of phase-I and phase-II enzymes controlled by aryl hydrocarbon receptor (AhR). Studies of competitive binding with 3H-labelled 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), 3-methylcholanthrene (3-MC) and benzo[a]pyrene (B[a]P) have shown that β-NF is a high-affinity ligand for AhR and also for polycyclic aromatic hydrocarbon (PAH)-binding protein, both soluble proteins of rat liver in 8 S and 4 S fractions, respectively, of sucrose gradients. This study examined binding of [3H]β-NF to liver cytosolic proteins of female Sprague-Dawley rats. Treatment of rats with β-NF, 3-MC, TCDD or α-naphthoflavone (α-NF) increased the specific [3H]β-NF binding to liver cytosol up to 125-fold that of vehicle (corn oil)-treated rats (< 100 fmol/mg of protein). Sucrose gradients revealed a large 4 S and a small 8 S peak of radioactivity from [3H]β-NF binding to cytosols of β-NF-, 3-MC-, TCDD- or α-NF-treated rats. Whereas co-incubation with the unlabelled β-NF eliminated both peaks, co-incubation with 2,3,7,8-tetrachlorodibenzofuran (TCDF) eliminated only the 8 S peak. The sucrose density gradient from [3H]TCDD binding to cytosol of β-NF- or TCDD-treated rats yielded a small 4 S and a larger 8 S peak; only the latter was abolished by co-incubation with TCDF. Thus, the patterns of sedimentation, distribution and elimination of radioactivity from the 8 S fraction of the liver cytosols from β-NF-, 3-MC-, TCDD- or α-NF-treated rats were characteristic for the AhR, whereas those from the 4 S fraction appeared specific for [3H]β-NF binding. The data indicate that potent AhR agonists, TCDD, 3-MC and β-NF, and to a lesser extent α-NF, a weak AhR agonist, induce a 4 S [3H]β-NF-binding protein in liver cytosol of female rats. α-NF, β-NF and 3-MC were effective competitors (80-85% inhibition) of the [3H]β-NF-specific binding to the β-NF-, 3 MC- or TCDD-induced 4 S protein, whereas several PAHs including B[a]P and benzo[e]pyrene were only weak competitors. The increased [3H]β-NF binding was not associated with glycine N-methyltransferase activity. Hence, the 4 S [3H]β-NF-binding protein described herein differs from the constitutive 4 S PAH-binding protein of rat liver cytosols in the inducibility by β-NF and 3-MC, ligand-binding characteristics, and lack of glycine N-methyltransferase activity. Gel filtration on Sephacryl of liver cytosols from β-NF-treated rats indicated a molecular mass of ≈ 42 kDa for [3H]β-NF-bound protein and suggested that it was derived from a large mass component that before the radioligand binding was eluted with the void volume of the gel and sedimented in a 7 S fraction of the sucrose gradient. The [3H]β-NF binding activity was not eluted with glutathione S-transferase Ya, aldehyde-3-dehydrogenase or DT-diaphorase [NAD(P)H: quinone oxidoreductase] activities, which are AhR-controlled and β-NF-inducible. Further studies are needed to determine the identity and function of this novel protein which may be involved either directly or indirectly (as a carrier protein) in xenobiotic metabolism in vivo.

scholarly journals Aryl Hydrocarbon Receptor Activation in Chronic Kidney Disease: Role of Uremic Toxins

Nephron ◽  
2017 ◽  
Vol 137 (1) ◽  
pp. 1-7 ◽  
Author(s):  
Jessyca S. Brito ◽  
Natália A. Borges ◽  
Marta Esgalhado ◽  
D''Angelo C. Magliano ◽  
Christophe O. Soulage ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Aryl Hydrocarbon Receptor ◽  
Receptor Activation ◽  
Uremic Toxins ◽  
Aryl Hydrocarbon

Aryl hydrocarbon receptor is activated in patients and mice with chronic kidney disease

2018 ◽  
Vol 93 (4) ◽  
pp. 986-999 ◽  
Author(s):  
Laetitia Dou ◽  
Stéphane Poitevin ◽  
Marion Sallée ◽  
Tawfik Addi ◽  
Bertrand Gondouin ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Aryl Hydrocarbon Receptor ◽  
Aryl Hydrocarbon

scholarly journals Aryl hydrocarbon receptor (AhR) and its endogenous agonist – indoxyl sulfate in chronic kidney disease

2017 ◽  
Vol 71 (1) ◽  
pp. 0-0 ◽  
Author(s):  
Tomasz Kamiński ◽  
Małgorzata Michałowska ◽  
Dariusz Pawlak
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Aryl Hydrocarbon Receptor ◽  
Biological Effects ◽  
P53 Protein ◽  
Free Fraction ◽  
High Reactivity ◽  
Indoxyl Sulfate ◽  
Aryl Hydrocarbon ◽  
Tryptophan Degradation

The indoxyl sulfate (IS, indoxyl sulphate) is the end product of dietary tryptophan degradation by indole pathway and significantly higher serum and tissue concentrations of this compound is observed in patients with impaired renal function. Despite the high albumin binding affinity, the remaining free fraction of IS has a number of biological effects related to the generation of oxidative stress andactivation of signaling pathways related to NF-кB, p53 protein, STAT3, TGF-β and Smad2/3. IS induces the inflammatory process, exerts nephrotoxic activity and is also a factor impairing the cardiovascular system.Its high concentrations are associated with the occurrence of cardiovascular incidents, whose frequency is significantly higher in patients with chronic kidney disease. Evaluation of the mechanisms that underlie the high reactivity of indoxyl sulfate and its biological effects showed that this compound is an agonist of the aryl hydrocarbon receptor (AhR). This receptor plays an important role in maintaining homeostasis Moreover, AhR exerts high transcriptional activity, so ligands of obciążethis receptor may exert different biological effects. The following paper describes the role of indoxyl sulfate as AhR ligand in the context of the excessive accumulation, which appears as one of the symptoms associated with chronic kidney disease.

P3493Uremic toxin induced endothelial dysfunction can be restored by inhibition of the aryl hydrocarbon receptor: implications for cardiovascular disease treatment in chronic kidney disease patients

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
A Kompa ◽  
C Nguyen ◽  
A J Edgley ◽  
D J Kelly
Keyword(s):  
Oxidative Stress ◽  
Cardiovascular Disease ◽  
Chronic Kidney Disease ◽  
Endothelial Dysfunction ◽  
Kidney Disease ◽  
Endothelial Function ◽  
Aryl Hydrocarbon Receptor ◽  
Uremic Toxin ◽  
Aryl Hydrocarbon ◽  
Endothelium Dependent Relaxation

Abstract Introduction Cardiovascular disease (CVD) mortality is significantly higher in chronic kidney disease (CKD) patients, with vascular calcification and atherosclerosis proving to be major contributors. Endothelial dysfunction is an early marker of atherosclerosis, triggered by oxidative stress and reduced nitric oxide production. The uremic toxin indoxyl sulphate (IS), a protein-bound non-dialyzable molecule derived from dietary tryptophan that accumulates in the blood of CKD patients, activates the aryl hydrocarbon receptor (AhR) promoting downstream cytochrome P450 1A1 (CYP1A1) expression mediating oxidative stress and potentially endothelial dysfunction. Targeting IS-induced AhR activation in the endothelium has not previously been examined and may represent a novel approach in targeting endothelial dysfunction. Purpose To assess the ability of the AhR antagonist, CH223191, to inhibit IS-mediated impairment of endothelial function and disruption of redox balance. Methods To assess endothelium-dependent relaxation, the thoracic aorta from adult male Sprague Dawley rats (N=10) were used in ex vivo experiments. Rings (5mm) from the aorta were exposed to IS (300μM) in the presence and absence of the AhR antagonist CH223191 (1 and 10μM), prior to pre-constriction of the vessel with phenylephrine (30μM) followed by relaxation with acetylcholine (ACh; 1nM-30μM). Control rings were not exposed to IS or CH223191 to determine normal endothelial responses to ACh. Responses were recorded with isometric force transducers connected to a PowerLab using Chart Software. Tissue sections from these rings were stained for superoxide using dihydroethidium. To examine key AhR-mediated oxidative stress pathways, separate aortic rings were exposed to IS and CH223191, under the above conditions, for 4 hours prior to RNA extraction and real-time PCR analysis. Results IS reduced the maximum level of endothelium-dependent relaxation (Rmax) to 50.17±2.71% (P<0.001) compared to control (86.00±3.93%). In the presence of IS, CH223191 restored Rmax to 77.74±3.14% (1μM) and 81.63±3.27% (10μM) (Figure, P<0.001). The potency of ACh, known as the pEC50 (negative logarithm of the effective concentration of ACh to produce a relaxation response of 50%), in control tissues (−7.08±0.07) was increased 100-fold following exposure of IS (−5.10±0.13; P<0.001). CH223191 restored pEC50 back to control values (1μM, −6.62±0.09; 10μM, −6.83±0.08; P<0.05). IS-exposed rings increased superoxide expression (P<0.001) and CYP1A1 gene expression (P<0.001), CH223191 restored expression of both superoxide (P<0.001) and CYP1A1 (P<0.001) back to control levels. CH223191 restores endothelial function Conclusion Our findings demonstrate the adverse impact of IS-mediated AhR activation on the vascular endothelium, where oxidative stress may play a critical role inducing endothelial dysfunction in the vasculature of the heart and kidneys. AhR inhibition may provide a novel therapy for CVD in the CKD setting. Acknowledgement/Funding National Health and Medical Research Council of Australia Program Grant

Sign in / Sign up

Export Citation Format

Share Document