Classification of Five Uremic Solutes according to Their Effects on Renal Tubular Cells

Edamatsu, Takeo; Fujieda, Ayako; Ezawa, Atsuko; Itoh, Yoshiharu

doi:10.1155/2014/512178

Cited by 20 publications

(21 citation statements)

References 48 publications

(73 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Four protein-bound uremic solutes were tested for their effects on total glutathione levels ( Fig 1 ). The concentration of each protein-bound uremic solute was set at a level high enough to inhibit cell growth or induce cell death, as determined in our previous study [ 17 ]. IS, PCS, and PhS significantly decreased glutathione levels, but IAA did not.…”

Section: Resultsmentioning

confidence: 99%

Phenyl sulfate, indoxyl sulfate and p-cresyl sulfate decrease glutathione level to render cells vulnerable to oxidative stress in renal tubular cells

2018

Self Cite

View full text Add to dashboard Cite

In chronic kidney disease patients, oxidative stress is generally associated with disease progression and pathogenesis of its comorbidities. Phenyl sulfate is a protein-bound uremic solute, which accumulates in chronic kidney disease patients, but little is known about its nature. Although many reports revealed that protein-bound uremic solutes induce reactive oxygen species production, the effects of these solutes on anti-oxidant level have not been well studied. Therefore, we examined the effects of protein-bound uremic solutes on glutathione levels. As a result, indoxyl sulfate, phenyl sulfate, and p-cresyl sulfate decreased glutathione levels in porcine renal tubular cells. Next we examined whether phenyl sulfate-treated cells becomes vulnerable to oxidative stress. In phenyl sulfate-treated cells, hydrogen peroxide induced higher rates of cell death than in control cells. Buthionine sulfoximine, which is known to decrease glutathione level, well mimicked the effect of phenyl sulfate. Finally, we evaluated a mixture of indoxyl sulfate, phenyl sulfate, and p-cresyl sulfate at concentrations comparable to the serum concentrations of hemodialysis patients, and we confirmed its decreasing effect on glutathione level. In conclusion, indoxyl sulfate, phenyl sulfate, and p-cresyl sulfate decrease glutathione levels, rendering the cells vulnerable to oxidative stress.

show abstract

Section: Resultsmentioning

confidence: 99%

Phenyl sulfate, indoxyl sulfate and p-cresyl sulfate decrease glutathione level to render cells vulnerable to oxidative stress in renal tubular cells

2018

Self Cite

View full text Add to dashboard Cite

show abstract

“…Hippuric acid is since long known as an inhibitor of drug protein binding [ 226 ] but other biological effects have been less extensively explored. The compound has been associated with kidney damage and to proximal tubular injury [ 227 , 228 , 229 ], an effect related to organic acid transporter uptake [ 228 ]. Of note, also several metabolomic studies linked hippuric acid to renal tubular damage [ 230 , 231 , 232 ].…”

Section: Protein Bound Compoundsmentioning

confidence: 99%

“…Indole acetic acid also induces proximal tubular injury after uptake via organic acid transporters, stimulates cellular free radical production [ 228 ] affecting cell viability [ 229 ] and accelerates progression of CKD in experimental animal studies [ 227 ]. Furthermore, indole acetic acid has been linked to a number of metabolic effects, such as the inhibition of uptake of digoxin [ 212 ] and renal glucuronidation [ 57 ].…”

Section: Protein Bound Compoundsmentioning

confidence: 99%

See 1 more Smart Citation

Biochemical and Clinical Impact of Organic Uremic Retention Solutes: A Comprehensive Update

Vanholder

Pletinck

Schepers

et al. 2018

Toxins

256

303

View full text Add to dashboard Cite

Abstract:In this narrative review, the biological/biochemical impact (toxicity) of a large array of known individual uremic retention solutes and groups of solutes is summarized. We classified these compounds along their physico-chemical characteristics as small water-soluble compounds or groups, protein bound compounds and middle molecules. All but one solute (glomerulopressin) affected at least one mechanism with the potential to contribute to the uremic syndrome. In general, several mechanisms were influenced for each individual solute or group of solutes, with some impacting up to 7 different biological systems of the 11 considered. The inflammatory, cardio-vascular and fibrogenic systems were those most frequently affected and they are one by one major actors in the high morbidity and mortality of CKD but also the mechanisms that have most frequently been studied. A scoring system was built with the intention to classify the reviewed compounds according to the experimental evidence of their toxicity (number of systems affected) and overall experimental and clinical evidence. Among the highest globally scoring solutes were 3 small water-soluble compounds [asymmetric dimethylarginine (ADMA); trimethylamine-N-oxide (TMAO); uric acid], 6 protein bound compounds or groups of protein bound compounds [advanced glycation end products (AGEs); p-cresyl sulfate; indoxyl sulfate; indole acetic acid; the kynurenines; phenyl acetic acid;] and 3 middle molecules [β 2 -microglobulin; ghrelin; parathyroid hormone). In general, more experimental data were provided for the protein bound molecules but for almost half of them clinical evidence was missing in spite of robust experimental data. The picture emanating is one of a complex disorder, where multiple factors contribute to a multisystem complication profile, so that it seems of not much use to pursue a decrease of concentration of a single compound.Keywords: uremic toxins; uremic toxicity; uremia; Chronic Kidney Disease; CKD; cardiovascular disease; inflammation; fibrosis; patho-physiology CKD; middle molecules; protein bound uremic solutes; water-soluble uremic solutes Key Contribution: This publication contains a comprehensive overview of the current knowledge on uremic toxicity, as well as an estimation of the degree of toxicity attributed to each individual toxin, and a classification according to the degree of known toxicity.

show abstract

“…However, there is less information on actions of IAA on cultured renal cells. In porcine proximal tubular LLC-PK1, IAA at a concentration of 250 µM reduced viability mainly through induction of apoptosis [ 27 ]. However, this concentration is not found in vivo.…”

Section: Metabolite Overload: Microbiota-generated Nephrotoxinsmentioning

confidence: 99%

Impact of Altered Intestinal Microbiota on Chronic Kidney Disease Progression

Castillo-Rodríguez

Fernández-Prado

Esteras

et al. 2018

Toxins

117

View full text Add to dashboard Cite

In chronic kidney disease (CKD), accumulation of uremic toxins is associated with an increased risk of CKD progression. Some uremic toxins result from nutrient processing by gut microbiota, yielding precursors of uremic toxins or uremic toxins themselves, such as trimethylamine N-Oxide (TMAO), p-cresyl sulphate, indoxyl sulphate and indole-3 acetic acid. Increased intake of some nutrients may modify the gut microbiota, increasing the number of bacteria that process them to yield uremic toxins. Circulating levels of nutrient-derived uremic toxins are associated to increased risk of CKD progression. This offers the opportunity for therapeutic intervention by either modifying the diet, modifying the microbiota, decreasing uremic toxin production by microbiota, increasing toxin excretion or targeting specific uremic toxins. We now review the link between nutrients, microbiota and uremic toxin with CKD progression. Specific focus will be placed on the generation specific uremic toxins with nephrotoxic potential, the decreased availability of bacteria-derived metabolites with nephroprotective potential, such as vitamin K and butyrate and the cellular and molecular mechanisms linking these toxins and protective factors to kidney diseases. This information provides a conceptual framework that allows the development of novel therapeutic approaches.

show abstract

Classification of Five Uremic Solutes according to Their Effects on Renal Tubular Cells

Cited by 20 publications

References 48 publications

Phenyl sulfate, indoxyl sulfate and p-cresyl sulfate decrease glutathione level to render cells vulnerable to oxidative stress in renal tubular cells

Phenyl sulfate, indoxyl sulfate and p-cresyl sulfate decrease glutathione level to render cells vulnerable to oxidative stress in renal tubular cells

Biochemical and Clinical Impact of Organic Uremic Retention Solutes: A Comprehensive Update

Impact of Altered Intestinal Microbiota on Chronic Kidney Disease Progression

Contact Info

Product

Resources

About