Indoxyl Sulfate Contributes to Uremic Sarcopenia by Inducing Apoptosis in Myoblasts

Rodrigues, Gabriela; Dellê, Humberto; Brito, Rodrigo Barbosa Oliveira; Cardoso, Vinícius Oliveira; Fernandes, Kristianne Porta Santos; Mesquita‐Ferrari, Raquel Agnelli; Cunha, Regiane Stafim da; Stinghen, Andréa Emília Marques; Dalboni, Maria Aparecida; Barreto, Fellype Carvalho

doi:10.1016/j.arcmed.2019.12.020

Cited by 21 publications

(21 citation statements)

References 42 publications

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“…Current clinical data indicated that the plasma level of PBUTs is rather low in the healthy population (HA: 16 μM, IS: 2 μM, PCS: 10 μM), but their average concentrations increase sharply in patients with CKD (HA: 398 μM, IS: 108 μM, PCS: 111 μM), as well as their highest concentrations (HA: 2,631 μM, IS: 940 μM, PCS: 219 μM) ( 27 , 37 ). Existing evidence indicated that PBUTs induced cellular apoptosis in the kidneys, brain, muscles, bones, and the heart ( 14 – 16 , 38 , 39 ), whereas no such evidence for the liver. In the present study, IS and PCS exerted limited proapoptotic effects on HepG2 cells, whereas 2,000 μM IS and PCS induced marked apoptosis in the THLE-2 cells.…”

Section: Discussionmentioning

confidence: 99%

“…Lin et al found IS caused apoptosis via oxidative stress and mitogen-activated protein kinase (MAPK) signaling inhibition in human astrocytes ( 15 ). IS also triggered apoptosis in the myoblast resulting in uremic sarcopenia ( 16 ). However, scarce research has been conducted to explore the proapoptotic effects of PBUTS on the liver, an extremely important organ to the metabolism, which attracted our scientific interest.…”

Section: Introductionmentioning

confidence: 99%

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Short-Chain Fatty Acids Alleviate Hepatocyte Apoptosis Induced by Gut-Derived Protein-Bound Uremic Toxins

Deng

et al. 2021

Front. Nutr.

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Chronic kidney disease (CKD) is characterized with the influx of uremic toxins, which impairs the gut microbiome by decreasing beneficial bacteria that produce short-chain fatty acids (SCFAs) and increasing harmful bacteria that produce gut-derived protein-bound uremic toxins (PBUTs). This study aimed to assess the proapoptotic effects of three major gut-derived PBUTs in hepatocytes, and the effects of SCFAs on apoptosis phenotype in vitro. HepG2 (human liver carcinoma cells) and THLE-2 (immortalized human normal liver cells) cell line were incubated with 0, 2, 20, 200, 2000 μM p-cresol sulfate (PCS), indoxyl sulfate (IS), and hippuric acid (HA), respectively, for 24 h. Flow cytometry analysis indicated that three uremic toxins induced varying degrees of apoptosis in hepatocytes and HA represented the highest efficacy. These phenotypes were further confirmed by western blot of apoptosis protein expression [Caspase-3, Caspase-9, B-cell lymphoma 2 (Bcl-2), and Bcl-2-associated X protein (Bax)]. Human normal hepatocytes (THLE-2) are more sensitive to PBUTs-induced apoptosis compared with human hepatoma cells (HepG2). Mechanistically, extracellular HA could enter hepatocytes, increase reactive oxygen species (ROS) generation, and decrease mitochondrial membrane potential dose-dependently in THLE-2 cells. Notably, coculture with SCFAs (acetate, propionate, butyrate) for 24 h significantly improved HA-induced apoptosis in THLE-2 cells, and propionate (500 μM) represented the highest efficacy. Propionate reduction of apoptosis was associated with improving mitochondria dysfunction and oxidative stress in a manner involving reducing Caspase-3 expression, ROS production, and increasing the Bcl-2/Bax level. As such, our studies validated PBUTs accumulation might be an important cause of liver dysfunction in patients with CKD, and supplementation of SCFAs might be a viable way to protect the liver for patients with CKD.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Short-Chain Fatty Acids Alleviate Hepatocyte Apoptosis Induced by Gut-Derived Protein-Bound Uremic Toxins

Deng

et al. 2021

Front. Nutr.

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“…Although the correctness of the concentrations analyzed has been questioned for some studies [ 18 , 19 ], a considerable number of high-quality studies underscore its multifunctional burden [ 13 ], including its roles in cardio-vascular disease, kidney and heart fibrosis, thrombogenicity, metabolic and hormonal dysfunction, inflammation and chronic kidney disease-mineral and bone disorder (CKD-MBD) [ 6 ]. More recently reported functional defects include neurotoxicity [ 20 , 21 , 22 ], intestinal epithelial [ 23 ] and hematologic alterations [ 24 , 25 , 26 ], sarcopenia [ 27 ], loss of muscle mass [ 28 ], disturbed drug removal [ 29 ], and accelerated cell senescence [ 30 ]. Undeniably, indoxyl sulfate is responsible for a plethora of negative effects, and it is ranked among the most important uremic toxins [ 6 ].…”

Section: Tryptophan Metabolites: the Good The Bad And The Ambivalentmentioning

confidence: 99%

What If Not All Metabolites from the Uremic Toxin Generating Pathways Are Toxic? A Hypothesis

Vanholder

Nigám

Burtey

et al. 2022

Toxins

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The topic of uremic toxicity has received broad attention from the nephrological community over the past few decades. An aspect that is much less often considered is the possibility that the metabolic pathways that generate uremic toxins also may produce molecules that benefit body functions. Here, we discuss this dualism based on the example of tryptophan-derived metabolites, which comprise elements that are mainly toxic, such as indoxyl sulfate, kynurenine and kynurenic acid, but also beneficial compounds, such as indole, melatonin and indole-3-propionic acid, and ambivalent (beneficial for some aspects and harmful for others) compounds such as serotonin. This dualism can also be perceived at the level of the main receptor of the tryptophan-derived metabolites, the aryl hydrocarbon receptor (AHR), which has also been linked to both harm and benefit. We hypothesize that these beneficial effects are the reason why uremic toxin generation remained preserved throughout evolution. This duality is also not unique for the tryptophan-derived metabolites, and in this broader context we discuss the remote sensing and signaling theory (RSST). The RSST proposes that transporters (e.g., organic anion transporter 1—OAT1; ATP-binding cassette transporter G—ABCG2) and drug metabolizing enzymes form a large network of proteins interacting to promote small molecule remote communication at the inter-organ (e.g., gut–liver–heart–brain–kidney) and inter-organismal (e.g., gut microbe–host) levels. These small molecules include gut microbe-derived uremic toxins as well as beneficial molecules such as those discussed here. We emphasize that this positive side of uremic metabolite production needs more attention, and that this dualism especially needs to be considered when assessing and conceiving of therapeutic interventions. These homeostatic considerations are central to the RSST and suggest that interventions be aimed at preserving or restoring the balance between positive and negative components rather than eliminating them all without distinction.

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“…Rodrigues et al have shown that IS has direct toxic effects on myoblast by the induction of cell apoptosis of murine cell lines dependent on three different IS concentrations in vitro study. However, no effect was observed on the markers of myoblast differentiation, MyoD and myogenin mRNA expression by real-time PCR, at any IS concentration [ 30 ]. PC is formed by gut bacterial fermentation of tyrosine and phenylalanine and has previously been described to promote the redistribution of total body fat and modify insulin resistance.…”

Section: Relationship Between Sarcopenic Obesity and Kidney Diseasementioning

confidence: 99%

The Role of Lifestyle Intervention, in Addition to Drugs, for Diabetic Kidney Disease with Sarcopenic Obesity

Chen

Liang

2022

Life

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Diabetic kidney disease is the leading cause of end-stage renal disease in developing and developed countries. The growing prevalence and clinical challenges of sarcopenic obesity have been associated with the frailty and disability of diabetic kidney disease. It has been reported that insulin resistance, chronic inflammation, enhanced oxidative stress and lipotoxicity contribute to the pathophysiology of muscle loss and visceral fat accumulation. Sarcopenic obesity, which is diagnosed with dual-energy X-ray absorptiometry, is associated with worse outcomes in kidney disease. Growing evidence indicates that adherence to healthy lifestyles, including low protein diet, proper carbohydrate control, vitamin D supplement, and regular physical training, has been shown to improve clinical prognosis. Based on the higher risk of sarcopenic-obesity-related renal function decline, it has led to the exploration and investigation of the pathophysiology, clinical aspects, and novel approach of these controversial issues in daily practice.

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Indoxyl Sulfate Contributes to Uremic Sarcopenia by Inducing Apoptosis in Myoblasts

Cited by 21 publications

References 42 publications

Short-Chain Fatty Acids Alleviate Hepatocyte Apoptosis Induced by Gut-Derived Protein-Bound Uremic Toxins

Short-Chain Fatty Acids Alleviate Hepatocyte Apoptosis Induced by Gut-Derived Protein-Bound Uremic Toxins

What If Not All Metabolites from the Uremic Toxin Generating Pathways Are Toxic? A Hypothesis

The Role of Lifestyle Intervention, in Addition to Drugs, for Diabetic Kidney Disease with Sarcopenic Obesity

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