Female AhR Knockout Mice Develop a Minor Renal Insufficiency in an Adenine-Diet Model of Chronic Kidney Disease

Makhloufi, Camélia; Nicolas, Frédéric; McKay, Nathalie; Fernandez, Samantha; Hache, Guillaume; Garrigue, Philippe; Brunet, Philippe; Guillet, Benjamin; Burtey, Stéphane; Poitevin, Stéphane

doi:10.3390/ijms21072483

Cited by 8 publications

(9 citation statements)

References 56 publications

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“…The conversion of administered adenine into 2,8-DHA by XDH is the key step in the induction of kidney injury by adenine feeding, which was demonstrated by the amelioration of kidney injury upon treatment with XDH inhibitors [ 31 , 32 ] and by the less severe kidney damage in mice with low expression level of XDH [ 33 ]. Thus, the differences in XDH expression levels observed in our study could modulate the severity of adenine-induced kidney damage and an increased XDH expression level could plausibly be the cause of exacerbated adenine-induced kidney damage in GF mice.…”

Section: Discussionmentioning

confidence: 99%

Germ-Free Conditions Modulate Host Purine Metabolism, Exacerbating Adenine-Induced Kidney Damage

Mishima

Ichijo

Kawabe

et al. 2020

Toxins

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Alterations in microbiota are known to affect kidney disease conditions. We have previously shown that germ-free conditions exacerbated adenine-induced kidney damage in mice; however, the mechanism by which this occurs has not been elucidated. To explore this mechanism, we examined the influence of germ-free conditions on purine metabolism and renal immune responses involved in the kidney damage. Germ-free mice showed higher expression levels of purine-metabolizing enzymes such as xanthine dehydrogenase, which converts adenine to a nephrotoxic byproduct 2,8-dihydroxyadenine (2,8-DHA). The germ-free mice also showed increased urinary excretion of allantoin, indicating enhanced purine metabolism. Metabolome analysis demonstrated marked differences in the purine metabolite levels in the feces of germ-free mice and mice with microbiota. Furthermore, unlike the germ-free condition, antibiotic treatment did not increase the expression of purine-metabolizing enzymes or exacerbate adenine-induced kidney damage. Considering renal immune responses, the germ-free mice displayed an absence of renal IL-17A expression. However, the adenine-induced kidney damage in wild-type mice was comparable to that in IL-17A-deficient mice, suggesting that IL-17A does not play a major role in the disease condition. Our results suggest that the enhanced host purine metabolism in the germ-free mice potentially promotes the conversion of the administered adenine into 2,8-DHA, resulting in exacerbated kidney damage. This further suggests a role of the microbiota in regulating host purine metabolism.

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Section: Discussionmentioning

confidence: 99%

Germ-Free Conditions Modulate Host Purine Metabolism, Exacerbating Adenine-Induced Kidney Damage

Mishima

Ichijo

Kawabe

et al. 2020

Toxins

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“…A study performed with knockout mice demonstrated that the animals AhR −/− had moderate renal insufficiency compared to the wild type genes in males, while the difference was even lower in females. This could be explained by the lower level of basal expression of the hepatic enzymes such as p450 cytochrome CYP2E1 and the sulfotransferase SULT1A1 involved in IS production, suggesting that AhR −/− mice have a weak capacity to metabolize indole into IS (Makhloufi et al, 2020).…”

Section: Clinical Approaches For Uremic Toxin Treatmentmentioning

confidence: 99%

Uremic Toxins: An Alarming Danger Concerning the Cardiovascular System

et al. 2021

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The kidneys and heart share functions with the common goal of maintaining homeostasis. When kidney injury occurs, many compounds, the so-called “uremic retention solutes” or “uremic toxins,” accumulate in the circulation targeting other tissues. The accumulation of uremic toxins such as p-cresyl sulfate, indoxyl sulfate and inorganic phosphate leads to a loss of a substantial number of body functions. Although the concept of uremic toxins is dated to the 1960s, the molecular mechanisms capable of leading to renal and cardiovascular injuries are not yet known. Besides, the greatest toxic effects appear to be induced by compounds that are difficult to remove by dialysis. Considering the close relationship between renal and cardiovascular functions, an understanding of the mechanisms involved in the production, clearance and overall impact of uremic toxins is extremely relevant for the understanding of pathologies of the cardiovascular system. Thus, the present study has as main focus to present an extensive review on the impact of uremic toxins in the cardiovascular system, bringing the state of the art on the subject as well as clinical implications related to patient’s therapy affected by chronic kidney disease, which represents high mortality of patients with cardiac comorbidities.

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“…25,27 In our pilot experiment, we observed significant renal dysfunction among CKD mice as measured by BUN at 4 weeks; however, we also observed a median body weight loss of 31.6% among CKD mice (Figure S1A). Although weight loss is a known limitation of the dietary adenine mouse model of CKD, 11,15,25 we sought to identify a treatment regimen that would result in significant renal dysfunction while minimizing weight loss given its potential as a confounder. We therefore developed a new regimen of intermittent 0.25% dietary adenine exposure by trending BUN and body weight measurements to achieve significant renal dysfunction while limiting weight loss (Figure 1A; Figure S1B and S1C).…”

Section: Dietary Adenine Induces Ckd In C57bl/6 Micementioning

confidence: 77%

Chronic Kidney Disease Induces Proarrhythmic Remodeling

King

Mintz

Lin

et al. 2023

Circ: Arrhythmia and Electrophysiology

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BACKGROUND: Patients with chronic kidney disease (CKD) are at increased risk of developing cardiac arrhythmogenesis and sudden cardiac death; however, the basis for this association is incompletely known. METHODS: Here, using murine models of CKD, we examined interactions between kidney disease progression and structural, electrophysiological, and molecular cardiac remodeling. RESULTS: C57BL/6 mice with adenine supplemented in their diet developed progressive CKD. Electrocardiographically, CKD mice developed significant QT prolongation and episodes of bradycardia. Optical mapping of isolated-perfused hearts using voltage-sensitive dyes revealed significant prolongation of action potential duration with no change in epicardial conduction velocity. Patch-clamp studies of isolated ventricular cardiomyocytes revealed changes in sodium and potassium currents consistent with action potential duration prolongation. Global transcriptional profiling identified dysregulated expression of cellular stress response proteins RBM3 (RNA-binding motif protein 3) and CIRP (cold-inducible RNA-binding protein) that may underlay the ion channel remodeling. Unexpectedly, we found that female sex is a protective factor in the progression of CKD and its cardiac sequelae. CONCLUSIONS: Our data provide novel insights into the association between CKD and pathologic proarrhythmic cardiac remodeling. Cardiac cellular stress response pathways represent potential targets for pharmacologic intervention for CKD-induced heart rhythm disorders.

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Female AhR Knockout Mice Develop a Minor Renal Insufficiency in an Adenine-Diet Model of Chronic Kidney Disease

Cited by 8 publications

References 56 publications

Germ-Free Conditions Modulate Host Purine Metabolism, Exacerbating Adenine-Induced Kidney Damage

Germ-Free Conditions Modulate Host Purine Metabolism, Exacerbating Adenine-Induced Kidney Damage

Uremic Toxins: An Alarming Danger Concerning the Cardiovascular System

Chronic Kidney Disease Induces Proarrhythmic Remodeling

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