Uremic Toxins Overload Accelerates Renal Damage in a Rat Model of Chronic Renal Failure

Satoh, Minoru; Hayashi, Hideo; Watanabe, Maki; Ueda, Kyoko; Yamato, Hideyuki; Yoshioka, Toshimasa; Motojima, Masaru

doi:10.1159/000074327

Cited by 100 publications

(71 citation statements)

References 18 publications

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“…It has been suggested that the uptake mechanism of HA plays a key role in the induction of HA nephrotoxicity (Satoh et al, 2003). Interestingly, the K p value in the brain was significantly greater for 5/6 Nx rats than for control rats.…”

Section: Discussionmentioning

confidence: 93%

“…Serum and cerebrospinal fluid concentrations of HA correlate positively with neurophysiological indices (Schoots et al, 1989), which suggests that HA induces neurological symptoms, perhaps via inhibition of organic anion transport at the blood-brain barrier (Ohtsuki et al, 2002) or blood-cerebrospinal fluid barrier (Porter et al, 1975). In addition, HA accelerates the renal damage associated with CRF (Satoh et al, 2003). Thus, HA can be classified as a uremic toxin and is consequently a compound of pharmacological interest.…”

mentioning

confidence: 99%

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Renal Clearance of Endogenous Hippurate Correlates with Expression Levels of Renal Organic Anion Transporters in Uremic Rats

Deguchi

Takemoto²,

Uehara³

et al. 2005

J Pharmacol Exp Ther

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Hippurate (HA) is a harmful uremic toxin that accumulates during chronic renal failure, and failure of the excretion system for uremic toxins is thought to be responsible. Recently, we reported that rat organic anion transporter 1 (rOat1) is the primary mediator of HA uptake in the kidney, and so now we have studied the pharmacokinetics and tissue distribution of HA after a single i.v. dose of HA to normal and 5/6 nephrectomized rats (5/6Nx rats). In control rats, the renal and biliary clearances of HA were 18.1 and 0.1 ml/min/kg, respectively. Plasma clearance decreased as dosage increased from 0.1 to 5 mg/kg, which suggests that renal tubular secretion is the primary route for elimination of HA. The plasma clearance of HA was significantly decreased in 5/6 Nx rats compared with normal rats. In 5/6 Nx rats, renal clearance of endogenous HA correlated more closely with clearance of p-aminohippurate than with that of creatinine. Protein expression of rOat1 and rOat3, assessed by Western blot analysis, was decreased in 5/6 Nx rats. Furthermore, in 5/6 Nx rats, the renal secretory clearance of endogenous HA correlated closely with protein expression of renal rOats. Thus, HA is primarily eliminated from the plasma via the kidney by active tubular secretion. The renal clearance of endogenous HA seems to be a useful indicator of changes in renal secretion that accompany the reduced levels of OAT protein in chronic renal failure.

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Section: Discussionmentioning

confidence: 93%

mentioning

confidence: 99%

Renal Clearance of Endogenous Hippurate Correlates with Expression Levels of Renal Organic Anion Transporters in Uremic Rats

Deguchi

Takemoto²,

Uehara³

et al. 2005

J Pharmacol Exp Ther

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“…They were also found to inhibit the active tubular secretion of organic acids by inhibiting renal organic anion transporters (Tsutsumi et al, 2002). As a consequence, the accumulation of these organic acids further stimulates the progression of chronic renal failure (Satoh et al, 2003). These uremic toxins might also be involved in altering thyroid function in uremic patients.…”

mentioning

confidence: 99%

Effects of Uremic Toxins on Hepatic Uptake and Metabolism of Erythromycin

Sun¹,

Huang²,

Frassetto³

et al. 2004

Drug Metab Dispos

116

115

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ABSTRACT:Hepatic clearance of erythromycin (Ery) is significantly reduced in patients with end stage renal disease. Since Ery is primarily eliminated via excretion of unchanged drug in the bile, we suspect that this change could be due to the effect of uremic toxins on hepatic uptake and/or efflux transporters. Using rat hepatocytes and microsomes as model proof of concept systems, we examined six uremic toxins, 3-carboxy-4-methyl-5-propyl-2-furan-propanoic acid (CMPF), indoxyl sulfate (IS), hippuric acid (HA), indole acetic acid (IA), guanidinosuccinic acid (GSA), and indoxyl-␤-D-glucuronide (IG), for their effects on Ery uptake and metabolism. Ery and the metabolite N-demethyl-Ery were measured by liquid chromatography/tandem mass spectrometry. The uptake of Ery by rat hepatocytes was markedly inhibited by rifampin and digoxin, but not by quinidine, suggesting that Oatp2 plays a major role in the uptake of Ery. At 50 M, CMPF significantly (p < 0.05) reduced hepatocyte accumulation of Ery and N-demethyl-Ery. At higher concentrations (>200 M), CMPF appears to also inhibit the enzymatic metabolism of Ery. In contrast, IS did not significantly inhibit the hepatocyte uptake of Ery, even at the highest concentration (800 M) tested, but reduced metabolite generation (p < 0.001). The other uremic toxins, HA, IA, IG, and GSA, did not affect either hepatic uptake or microsomal metabolism of Ery. CMPF, IS, and HA were shown not to inhibit differential P-glycoprotein transport of Ery in cellular systems. Our results suggest that CMPF can directly inhibit the uptake of Ery by inhibiting Oatp2, whereas IS is more likely to inhibit the enzymatic metabolism of Ery.

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“…Bar 5 20 mm. Vanholder et al 2001;Motojima et al 2002;Ohtsuki et al 2002;Tsutsumi et al 2002;Satoh et al 2003;Vanholder et al 2003;Dou et al 2004). Recently, transport of these organic anions by rOAT1/hOAT1 has been demonstrated in kidney epithelial cell lines (Deguchi et al 2004).…”

Section: The Journal Of Histochemistry and Cytochemistrymentioning

confidence: 99%

Alteration in Renal Organic Anion Transporter 1 After Ischemia/Reperfusion in Cadaveric Renal Allografts

Kwon

Hong

Blouch

2007

J Histochem Cytochem.

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We have previously shown that postischemic injury to renal allografts results in profound impairment of p-aminohippuric acid (PAH) extraction. To elucidate the cellular integrity of the human organic anion transporter 1 (hOAT1) in postischemic acute renal failure (ARF), immunohistochemical analysis of hOAT1 was performed in cadaveric renal allografts using confocal microscopy for three-dimensional reconstruction of serial optical images. Biopsy samples were obtained from 10 cadaveric renal allografts 1 hr after reperfusion during transplant operation. Control tissues were obtained from four living donors of healthy kidneys immediately before an arterial clamp was applied to the renal artery. Control tissues demonstrated hOAT1 distributed to basolateral membrane of proximal tubule cells. In contrast, maldistribution of hOAT1 to cytoplasm and/or diminution of the protein was noted in cadaveric allografts. Characteristics of maldistribution were variable: disappearance of lateral distribution, diffuse cytoplasmic aggregates, apical cytoplasmic aggregates, and disappearance of the staining. In addition, iothalamate and PAH clearances were performed on posttransplant days 3–7 in 18 recipients of a cadaveric renal allograft. PAH clearance was depressed <250 ml/min in all but three subjects. We conclude that reperfused, transplanted kidneys exhibit maldistribution of hOAT1 in proximal tubule cells, resulting in impairment of PAH clearance. This manuscript contains online supplemental material at http://www.jhc.org . Please visit this article online to view these materials.

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Uremic Toxins Overload Accelerates Renal Damage in a Rat Model of Chronic Renal Failure

Cited by 100 publications

References 18 publications

Renal Clearance of Endogenous Hippurate Correlates with Expression Levels of Renal Organic Anion Transporters in Uremic Rats

Renal Clearance of Endogenous Hippurate Correlates with Expression Levels of Renal Organic Anion Transporters in Uremic Rats

Effects of Uremic Toxins on Hepatic Uptake and Metabolism of Erythromycin

Alteration in Renal Organic Anion Transporter 1 After Ischemia/Reperfusion in Cadaveric Renal Allografts

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