Organic anion transporters play an important role in the uptake of p-cresyl sulfate, a uremic toxin, in the kidney

Miyamoto, Yohei; Watanabe, Hiroshi; Noguchi, Tsuyoshi; Kotani, Shunsuke; Nakajima, Makoto; Kadowaki, Daisuke; Otagiri, Masaki; Maruyama, Toru

doi:10.1093/ndt/gfq785

Cited by 84 publications

(86 citation statements)

References 24 publications

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“…Uptake of p-cresyl sulfate (100 mmol/L) in rat renal cortical slices was inhibited significantly ( 50%-80%) by 1,000 mmol/L (10-fold excess) benzylpenicillin, estrone sulfate, PAH, CMPF, hippuric acid, or indoxyl sulfate. 33 These data are consistent with rOat1-and rOat3-mediated transport of p-cresyl sulfate, but are not conclusive. Other organic anion transporters, which could play a role in the transport of p-cresyl sulfate, are expressed in the kidney (eg, OATP4C1 [SLCO4C1]).…”

Section: Potential Of Uremic Toxins To Cause Clinically Relevant Intementioning

confidence: 77%

The Kidney and Uremic Toxin Removal: Glomerulus or Tubule?

Masereeuw

Mutsaers

Toyohara³

et al. 2014

Seminars in Nephrology

134

122

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This article appeared in a journal published by Elsevier. The attached copy is furnished to the author for internal non-commercial research and education use, including for instruction at the authors institution and sharing with colleagues.Other uses, including reproduction and distribution, or selling or licensing copies, or posting to personal, institutional or third party websites are prohibited.

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Section: Potential Of Uremic Toxins To Cause Clinically Relevant Intementioning

confidence: 77%

The Kidney and Uremic Toxin Removal: Glomerulus or Tubule?

Masereeuw

Mutsaers

Toyohara³

et al. 2014

Seminars in Nephrology

134

122

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“…Furthermore, fractional excretion was lower in patients with advanced CKD, thus also pointing to saturation of tubular transport for PCS and PCG. Although mechanisms underlying tubular secretion of PCS are increasingly being unraveled (13,14,27), less is known about renal handling of PCG. Recent data point to potential involvement of breast cancer resistance protein and multidrug resistance-associated protein 4 for tubular transport of PCG, whereas secretion of PCS may depend on multidrug resistance-associated protein 4 but not on breast cancer resistance protein (23).…”

Section: Discussionmentioning

confidence: 99%

“…Although it can be hypothesized that this imbalance is caused by differences in phase 2 metabolism, possibly influenced by renal dysfunction, this has not been studied to date. Furthermore, renal handling of PCG is unknown but may be different compared with PCS, which mainly depends on tubular secretion (13)(14)(15)(16). In addition, although it is well established that serum PCS is highly protein bound (17,18), protein binding characteristics of serum PCG are less clear, possibly contributing to differential renal clearance of PCS and PCG.…”

Section: Introductionmentioning

confidence: 99%

Metabolism, Protein Binding, and Renal Clearance of Microbiota–Derived p-Cresol in Patients with CKD

Poesen

Evenepoel

Loor

et al. 2016

CJASN

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Background and objectives Colonic microbial metabolism substantially contributes to uremic retention solutes in CKD. p-Cresyl sulfate is the main representative of this group of solutes, relating to adverse outcomes. Other than sulfate conjugation, p-cresol is subjected to endogenous glucuronide conjugation. Whether the balance between sulfate and glucuronide conjugation is relevant in CKD is unexplored.Design, setting, participants, & measurements We prospectively followed 488 patients with CKD stages 1-5 (enrollment between November of 2005 and September of 2006; follow-up until December of 2010). Serum and urine levels of p-cresyl sulfate and p-cresyl glucuronide were measured using liquid chromatography-mass spectrometry. Total amount of microbial p-cresol was calculated by the sum of serum p-cresyl sulfate and p-cresyl glucuronide. Outcome analysis was performed for mortality and cardiovascular disease.Results Serum p-cresyl sulfate was a median of 193.0-fold (interquartile range, 121.1-296.6) higher than serum p-cresyl glucuronide, with a significant correlation between eGFR and proportion of serum p-cresyl sulfate to glucuronide (rho=0.23; P=0.001). There was also a significant correlation between eGFR and proportion of 24-hour urinary excretion of p-cresyl sulfate to glucuronide (rho=0.32; P,0.001). Higher serum p-cresol and lower proportion of serum p-cresyl sulfate to glucuronide were jointly and significantly associated with mortality (hazard ratio per SD higher, 1.58; 95% confidence interval, 1.10 to 2.29; P=0.01 and hazard ratio, 0.65; 95% confidence interval, 0.47 to 0.89; P,0.01, respectively) and cardiovascular disease (hazard ratio, 1.68; 95% confidence interval, 1.27 to 2.22; P,0.001 and hazard ratio, 0.55; 95% confidence interval, 0.42 to 0.72; P,0.001, respectively) after adjustment for eGFR, Framingham risk factors, mineral bone metabolism markers, C-reactive protein, and albumin.Conclusions p-Cresol shows a preponderance of sulfate conjugation, although a relatively diminished sulfotransferase activity can be suggested in patients with advanced CKD. Along with total p-cresol burden, a relative shift from sulfate to glucuronide conjugation is independently associated with mortality and cardiovascular disease, warranting increased focus to the dynamic interplay between microbial and endogenous metabolism.

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“…In good agreement, insulin stimulation induces a marked increase in the level of p85 protein co-immunoprecipitated with IRS-1 (1.7-fold compared with unstimulated cells), whereas PCS significantly decreased the level of p85 protein co-immunoprecipitated with IRS-1 ( Figure 5E). Miyamoto et al 29 recently proposed that in renal cells, PCS enters the cell via organic anion transporters (OAT), especially OAT3. We pretreated C2C12 muscle cells with probenecid (1 mM, 1 hour), a potent inhibitor of OAT family, before incubation with PCS.…”

Section: Pcs Impairs Insulin-induced Glucose Uptake and Signaling In mentioning

confidence: 99%

p-Cresyl Sulfate Promotes Insulin Resistance Associated with CKD

Koppe

Pillon

Vella

et al. 2013

Journal of the American Society of Nephrology

229

175

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The mechanisms underlying the insulin resistance that frequently accompanies CKD are poorly understood, but the retention of renally excreted compounds may play a role. One such compound is p-cresyl sulfate (PCS), a protein-bound uremic toxin that originates from tyrosine metabolism by intestinal microbes. Here, we sought to determine whether PCS contributes to CKD-associated insulin resistance. Administering PCS to mice with normal kidney function for 4 weeks triggered insulin resistance, loss of fat mass, and ectopic redistribution of lipid in muscle and liver, mimicking features associated with CKD. Mice treated with PCS exhibited altered insulin signaling in skeletal muscle through ERK1/2 activation. In addition, exposing C2C12 myotubes to concentrations of PCS observed in CKD caused insulin resistance through direct activation of ERK1/2. Subtotal nephrectomy led to insulin resistance and dyslipidemia in mice, and treatment with the prebiotic arabino-xylo-oligosaccharide, which reduced serum PCS by decreasing intestinal production of p-cresol, prevented these metabolic derangements. Taken together, these data suggest that PCS contributes to insulin resistance and that targeting PCS may be a therapeutic strategy in CKD.

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Organic anion transporters play an important role in the uptake of p-cresyl sulfate, a uremic toxin, in the kidney

Abstract: The findings of the present study strongly suggest that PCS serves as a substrate for OATs, is preferentially recognized by OAT3 and plays a key role in the renal tubular secretion process.

Cited by 84 publications

References 24 publications

The Kidney and Uremic Toxin Removal: Glomerulus or Tubule?

The Kidney and Uremic Toxin Removal: Glomerulus or Tubule?

Metabolism, Protein Binding, and Renal Clearance of Microbiota–Derived p-Cresol in Patients with CKD

p-Cresyl Sulfate Promotes Insulin Resistance Associated with CKD

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