The Dual Roles of Protein-Bound Solutes as Toxins and Signaling Molecules in Uremia

Masereeuw, Rosalinde

doi:10.3390/toxins14060402

Cited by 4 publications

(5 citation statements)

References 42 publications

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“…Key transporters, OAT1 and OAT3, expressed on the basolateral membrane of proximal renal tubules, are crucial for the renal uptake of endogenous metabolites, including uremic toxins, in exchange for α-ketoglutarate. Additionally, efflux pumps like BCRP and MRP2/4 concurrently transport these substances into the tubular lumen, facilitating their final removal [ 43 , 44 ]. In CKD patients, a decrease in transporters appears to be evident, as supported by the study of Naud et al [ 45 ].…”

Section: The Kidney–gut Axis: a Potential Connection Between Gut Dysb...mentioning

confidence: 99%

The Kidney–Gut Axis as a Novel Target for Nutritional Intervention to Counteract Chronic Kidney Disease Progression

Cabała,

Ożgo,

Herosimczyk

2024

Metabolites

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A well-balanced diet is integral for overall health, aiding in managing key risk factors for kidney damage like hypertension while supplying necessary precursors for metabolite production. Dietary choices directly influence the composition and metabolic patterns of the gut microbiota, showing promise as therapeutic tools for addressing various health conditions, including chronic kidney diseases (CKD). CKD pathogenesis involves a decline in the glomerular filtration rate and the retention of nitrogen waste, fostering gut dysbiosis and the excessive production of bacterial metabolites. These metabolites act as uremic toxins, contributing to inflammation, oxidative stress, and tissue remodeling in the kidneys. Dietary interventions hold significance in reducing oxidative stress and inflammation, potentially slowing CKD progression. Functional ingredients, nutrients, and nephroprotective phytoconstituents could modulate inflammatory pathways or impact the gut mucosa. The “gut–kidney axis” underscores the impact of gut microbes and their metabolites on health and disease, with dysbiosis serving as a triggering event in several diseases, including CKD. This review provides a comprehensive overview, focusing on the gut–liver axis, and explores well-established bioactive substances as well as specific, less-known nutraceuticals showing promise in supporting kidney health and positively influencing CKD progression.

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Section: The Kidney–gut Axis: a Potential Connection Between Gut Dysb...mentioning

confidence: 99%

The Kidney–Gut Axis as a Novel Target for Nutritional Intervention to Counteract Chronic Kidney Disease Progression

Cabała,

Ożgo,

Herosimczyk

2024

Metabolites

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“…PBUTs are removed by proximal tubule cells in healthy kidneys through active secretion involving transporter proteins but poorly removed with kidney dysfunction [ 111 ]. Current dialysis therapy is limited because of the high binding to plasma proteins, with albumin being the primary carrier protein, and only a small free fraction is available for transfer across dialyzer membranes [ 3 , 4 ].…”

Section: Protein-bound Uremic Toxins Promote Fibrosis By Accelerating...mentioning

confidence: 99%

“…Uremic toxins are metabolites that accumulate during kidney disease. Protein-bound uremic toxins (PBUTs) are mostly less than 500 Da but are poorly removed with kidney dysfunction, as they are tightly bound to plasma proteins and can also hardly cross dialyzer membranes [ 3 , 4 ]. PBUTs, such as indoxyl sulfate (IS) and p-cresol sulfate (PCS), accumulate in CKD, maintaining and reinforcing CKD and kidney fibrosis [ 5 , 6 ].…”

Section: Introductionmentioning

confidence: 99%

Protein-Bound Uremic Toxins in Senescence and Kidney Fibrosis

Yang,

Mihajlovic,

Masereeuw

2023

Biomedicines

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Chronic kidney disease (CKD) is a progressive condition of kidney dysfunction due to diverse causes of injury. In healthy kidneys, protein-bound uremic toxins (PBUTs) are cleared from the systemic circulation by proximal tubule cells through the concerted action of plasma membrane transporters that facilitate their urinary excretion, but the endogenous metabolites are hardly removed with kidney dysfunction and may contribute to CKD progression. Accumulating evidence suggests that senescence of kidney tubule cells influences kidney fibrosis, the common endpoint for CKD with an excessive accumulation of extracellular matrix (ECM). Senescence is a special state of cells characterized by permanent cell cycle arrest and limitation of proliferation, which promotes fibrosis by releasing senescence-associated secretory phenotype (SASP) factors. The accumulation of PBUTs in CKD causes oxidative stress and increases the production of inflammatory (SASP) factors that could trigger fibrosis. Recent studies gave some clues that PBUTs may also promote senescence in kidney tubular cells. This review provides an overview on how senescence contributes to CKD, the involvement of PBUTs in this process, and how kidney senescence can be studied. Finally, some suggestions for future therapeutic options for CKD while targeting senescence are given.

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“…With respect to renal excretion, the transport proteins organic cation transporter (OCT) 2 ( SLC22A2 ), multidrug and toxin extrusion proteins (MATE) 1 and 2‐K ( SLC47A1 and SLC47A2 , respectively), and organic anion transporters (OATs) 1 and 3 ( SLC22A6 and SLC22A8 , respectively) are of major importance. A broad range of endogenous compounds has been proposed as biomarkers for the above‐named transporters based on in vitro studies, showing that the putative biomarker is a substrate of the respective transporter and/or based on an impact of a known transporter inhibitor on the pharmacokinetics of the putative biomarker in animal models and/or humans 13–17 …”

mentioning

confidence: 99%

“…A broad range of endogenous compounds has been proposed as biomarkers for the above-named transporters based on in vitro studies, showing that the putative biomarker is a substrate of the respective transporter and/or based on an impact of a known transporter inhibitor on the pharmacokinetics of the putative biomarker in animal models and/or humans. [13][14][15][16][17] Putative biomarkers need to be fully characterized regarding multiple aspects before they can be considered as valid biomarkers for transporter-mediated DDI (see refs. [13][14][15] for recent reviews).…”

mentioning

confidence: 99%

A Metabolomic Analysis of Sensitivity and Specificity of 23 Previously Proposed Biomarkers for Renal Transporter‐Mediated Drug‐Drug Interactions

Gessner

Müller

Wenisch

et al. 2023

Clin Pharma and Therapeutics

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Endogenous biomarkers are discussed as tools for detection of drug‐drug interactions mediated by renal transport proteins, such as organic cation transporter 2 (OCT2), multidrug and toxin extrusion proteins (MATE1 and MATE2‐K) and organic anion transporters (OAT1 and OAT3). Whereas sensitivity of some endogenous biomarkers against at least one clinical transporter inhibitor has frequently been shown, intrastudy comparisons of the extent of effects of inhibitors on different biomarkers are frequently lacking. Moreover, in vivo specificity of such discussed biomarkers has frequently not been studied. We therefore investigated changes of ten previously described putative biomarkers for inhibition of OCT2/MATEs, as well as 15 previously described putative biomarkers for OATs in human plasma and urine samples of healthy volunteers in response to treatment with four inhibitors of transport proteins [verapamil (P‐glycoprotein), rifampin (organic anion transporting polypeptides), cimetidine (OCT2/MATEs), and probenecid (OATs)]. Two of the putative biomarkers had been suggested for both OCT2/MATEs and OATs. All substances were unequivocally identified in an untargeted metabolomics assay. The OCT2/MATE biomarkers choline and trimethylamine N‐oxide were both sensitive and specific (median log2‐fold changes ‐1.18 in estimated renal elimination and ‐0.85 in urinary excretion, respectively). For renal OATs, indoleacetyl glutamine and indoleacetic acid (median log2‐fold changes ‐3.77 and ‐2.85 in estimated renal elimination, respectively) were the candidates for sensitive and specific biomarkers with the most extensive change, followed by taurine, indolelactic acid and hypoxanthine. This comprehensive study adds further knowledge on sensitivity and specificity of 23 previously described biomarkers of renal OCT2/MATE‐ and OAT‐mediated drug‐drug interactions.

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The Dual Roles of Protein-Bound Solutes as Toxins and Signaling Molecules in Uremia

Cited by 4 publications

References 42 publications

The Kidney–Gut Axis as a Novel Target for Nutritional Intervention to Counteract Chronic Kidney Disease Progression

The Kidney–Gut Axis as a Novel Target for Nutritional Intervention to Counteract Chronic Kidney Disease Progression

Protein-Bound Uremic Toxins in Senescence and Kidney Fibrosis

A Metabolomic Analysis of Sensitivity and Specificity of 23 Previously Proposed Biomarkers for Renal Transporter‐Mediated Drug‐Drug Interactions

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