Protein-Bound Uremic Toxins Induce Reactive Oxygen Species-Dependent and Inflammasome-Mediated IL-1β Production in Kidney Proximal Tubule Cells

Mihajlovic, Milos; Krebber, Merle M.; Yang, Yi; Ahmed, Sabbir; Lozovanu, Valeria; Andreeva, Daria; Verhaar, Marianne C.; Masereeuw, Rosalinde

doi:10.3390/biomedicines9101326

Cited by 15 publications

(17 citation statements)

References 76 publications

(93 reference statements)

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“…Pathogenic mechanisms of oxidative stress in CKD have extensively been reported and discussed [ 100 , 101 , 102 , 103 , 104 , 105 ]. Specific factors, both positive and negative, that influence the overall extent of oxidative stress in human CKD are, for example, related to treatment modality or medication [ 106 , 107 ] and uremic toxin accumulation [ 108 , 109 , 110 ]. The differential expression of antioxidant and mitochondrial enzymes such as superoxide dismutase 1/2 (SOD1/2), thiosulfate sulfurtransferase (rhodanese), or GPx in dependence of CKD stage or severity is well-described [ 111 , 112 , 113 , 114 ].…”

Section: Clinical Data Of Nrf2 Activation In Human Ckdmentioning

confidence: 99%

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Nrf2 Activation in Chronic Kidney Disease: Promises and Pitfalls

et al. 2022

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The nuclear factor erythroid 2-related factor 2 (Nrf2) protects the cell against oxidative damage. The Nrf2 system comprises a complex network that functions to ensure adequate responses to redox perturbations, but also metabolic demands and cellular stresses. It must be kept within a physiologic activity range. Oxidative stress and alterations in Nrf2-system activity are central for chronic-kidney-disease (CKD) progression and CKD-related morbidity. Activation of the Nrf2 system in CKD is in multiple ways related to inflammation, kidney fibrosis, and mitochondrial and metabolic effects. In human CKD, both endogenous Nrf2 activation and repression exist. The state of the Nrf2 system varies with the cause of kidney disease, comorbidities, stage of CKD, and severity of uremic toxin accumulation and inflammation. An earlier CKD stage, rapid progression of kidney disease, and inflammatory processes are associated with more robust Nrf2-system activation. Advanced CKD is associated with stronger Nrf2-system repression. Nrf2 activation is related to oxidative stress and moderate uremic toxin and nuclear factor kappa B (NF-κB) elevations. Nrf2 repression relates to high uremic toxin and NF-κB concentrations, and may be related to Kelch-like ECH-associated protein 1 (Keap1)-independent Nrf2 degradation. Furthermore, we review the effects of pharmacological Nrf2 activation by bardoxolone methyl, curcumin, and resveratrol in human CKD and outline strategies for how to adapt future Nrf2-targeted therapies to the requirements of patients with CKD.

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Section: Clinical Data Of Nrf2 Activation In Human Ckdmentioning

confidence: 99%

“…Indoxyl sulfate , a metabolite of the tryptophan pathway, is one of the very important uremic toxins [ 118 ]. Indoxyl sulfate (43 mg/L) induced the production of ROS in proximal tubule epithelial cells [ 109 ]. In addition, indoxyl sulfate activates the arylhydrocarbon receptor (AhR).…”

Section: Clinical Data Of Nrf2 Activation In Human Ckdmentioning

confidence: 99%

Nrf2 Activation in Chronic Kidney Disease: Promises and Pitfalls

et al. 2022

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“…The NLRP3 in ammasome is a group of pattern recognition receptors involved in various innate immune responses to both microbial and non-microbial stimuli [23]. Previous research has indicated that the NLRP3 in ammasome is implicated in the regulation of intestinal homeostasis and can be activated by bacterial products such as lipopolysaccharide (LPS) and gutderived uremic toxins like indoxyl sulfate (IS) [24][25][26]. Therefore, it is reasonable to hypothesize that the NLRP3 in ammasome participates in the cross-talk between the microbiota, in ammation, and kidney axis.…”

Section: Introductionmentioning

confidence: 99%

Gut microbiota dysbiosis in hyperuricemia promotes renal injury through the activation of NLRP3 inflammasome

Zhou,

Ji,

Chen

et al. 2023

Preprint

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Background The prevalence of hyperuricemia (HUA), a metabolic disorder characterized by elevated levels of uric acid, is on the rise, and it is frequently associated with renal injury. Gut microbiota and gut-derived uremic toxins as the critical mediators in the gut-kidney axis that cause damage to kidney function. Gut dysbiosis has been implicated in various kidney diseases. However, the role of microbiota in HUA-induced renal injury and the underlying mechanism reminds unknown. Results Uricase-knockout(UOX−/−) rats is a model of HUA exhibited renal function impairment, renal tubular injury, fibrosis, activation of NLRP3 inflammasome and compromised intestinal barrier functions. The 16S rRNA sequencing and function prediction revealed an abnormal gut microbiota profile and activation of pathways associated with uremic toxin production. Metabolomic analysis further confirmed the increase of renal uremic toxins. To provide additional evidence, fecal microbiota transplantation (FMT) was conducted, where mice recolonized with HUA microbiota exhibited severe renal injury and compromised intestinal barrier functions following renal ischemia/reperfusion (I/R) surgery. Notably, in NLRP3-knockout (NLRP3-/-) I/R mice, the deleterious effects of HUA microbiota on renal injury and intestinal barrier were eliminated. Conclusion Our results demonstrate that HUA-induced gut dysbiosis promotes the development of renal injury, possibly by promoting the production of gut-derived uremic toxins and subsequently activating NLRP3 inflammasome. Our data suggest a potential therapeutic strategy for the treatment of renal disease by targeting the microbiota and NLRP3 inflammasome.

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“…In CKD patients, activation of the NF-ĸB pathway due to elevated levels of microbial metabolites such as p-cresol, trimethylamine and indole propionic acid leads to systemic inflammation [ 33 , 34 ] which translates to a high risk of atherosclerosis. The accumulation of uremic metabolites leads to reactive oxygen species (ROS) formation in the kidney epithelial cells by inflammasome-mediated IL-1β production [ 35 ].…”

Section: Introductionmentioning

confidence: 99%

Homeostasis in the Gut Microbiota in Chronic Kidney Disease

Bhargava

Merckelbach

Noels

et al. 2022

Toxins

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The gut microbiota consists of trillions of microorganisms, fulfilling important roles in metabolism, nutritional intake, physiology and maturation of the immune system, but also aiding and abetting the progression of chronic kidney disease (CKD). The human gut microbiome consists of bacterial species from five major bacterial phyla, namely Firmicutes, Bacteroidetes, Actinobacteria, Proteobacteria, and Verrucomicrobia. Alterations in the members of these phyla alter the total gut microbiota, with a decline in the number of symbiotic flora and an increase in the pathogenic bacteria, causing or aggravating CKD. In addition, CKD-associated alteration of this intestinal microbiome results in metabolic changes and the accumulation of amines, indoles and phenols, among other uremic metabolites, which have a feedforward adverse effect on CKD patients, inhibiting renal functions and increasing comorbidities such as atherosclerosis and cardiovascular diseases (CVD). A classification of uremic toxins according to the degree of known toxicity based on the experimental evidence of their toxicity (number of systems affected) and overall experimental and clinical evidence was selected to identify the representative uremic toxins from small water-soluble compounds, protein-bound compounds and middle molecules and their relation to the gut microbiota was summarized. Gut-derived uremic metabolites accumulating in CKD patients further exhibit cell-damaging properties, damage the intestinal epithelial cell wall, increase gut permeability and lead to the translocation of bacteria and endotoxins from the gut into the circulatory system. Elevated levels of endotoxins lead to endotoxemia and inflammation, further accelerating CKD progression. In recent years, the role of the gut microbiome in CKD pathophysiology has emerged as an important aspect of corrective treatment; however, the mechanisms by which the gut microbiota contributes to CKD progression are still not completely understood. Therefore, this review summarizes the current state of research regarding CKD and the gut microbiota, alterations in the microbiome, uremic toxin production, and gut epithelial barrier degradation.

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Protein-Bound Uremic Toxins Induce Reactive Oxygen Species-Dependent and Inflammasome-Mediated IL-1β Production in Kidney Proximal Tubule Cells

Cited by 15 publications

References 76 publications

Nrf2 Activation in Chronic Kidney Disease: Promises and Pitfalls

Nrf2 Activation in Chronic Kidney Disease: Promises and Pitfalls

Gut microbiota dysbiosis in hyperuricemia promotes renal injury through the activation of NLRP3 inflammasome

Homeostasis in the Gut Microbiota in Chronic Kidney Disease

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