Excretion of para‐aminohippurate in the isolated perfused rat kidney: net secretion and net reabsorption.

MacDougall, Margaret; Wiegmann, Thomas

doi:10.1113/jphysiol.1988.sp017012

Cited by 11 publications

(4 citation statements)

References 26 publications

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“…Concentrations of inulin and ES were determined by liquid scintillation counting, and concentration of PAH was determined with a colorimetric assay following precipitation of plasma proteins, as previously described (47,48). In the case of plasma ES, which, unlike PAH (49,50), is highly protein-bound (51,52), both protein-free and total concentrations were measured for each individual mouse in the experiment (protein-free concentrations were determined using centrifugal filter devices (Microton; Millipore Corp., Bedford, MA)).…”

Section: Methodsmentioning

confidence: 99%

Decreased Renal Organic Anion Secretion and Plasma Accumulation of Endogenous Organic Anions in OAT1 Knock-out Mice

Eraly

Vallon

Vaughn

et al. 2006

Journal of Biological Chemistry

217

246

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The "classical" organic anion secretory pathway of the renal proximal tubule is critical for the renal excretion of the prototypic organic anion, para-aminohippurate, as well as of a large number of commonly prescribed drugs among other significant substrates. Organic anion transporter 1 (OAT1), originally identified as NKT (Lopez-Nieto, C. E., You, G., Bush, K. T., Barros, E. J. G., Beier, D. R., and Nigam, S. K. (1997) J. Biol. Chem. 272, 6471-6478), has physiological properties consistent with a role in this pathway. However, several other transporters (e.g. OAT2, OAT3, and MRP1) have also been proposed as important PAH transporters on the basis of in vitro studies; therefore, the relative contribution of OAT1 has remained unclear. We have now generated a colony of OAT1 knockout mice, permitting elucidation of the role of OAT1 in the context of these other potentially functionally redundant transporters. We find that the knock-out mice manifest a profound loss of organic anion transport (e.g. para-aminohippurate) both ex vivo (in isolated renal slices) as well as in vivo (as indicated by loss of renal secretion). In the case of the organic anion, furosemide, loss of renal secretion in the knock-out results in impaired diuretic responsiveness to this drug. These results indicate a critical role for OAT1 in the functioning of the classical pathway. In addition, we have determined the levels of ϳ60 endogenous organic anions in the plasma and urine of wild-type and knock-out mice. This has led to identification of several compounds with significantly higher plasma concentrations and/or lower urinary concentrations in knock-out mice, suggesting the involvement of OAT1 in their renal secretion. We have also demonstrated in xenopus oocytes that some of these compounds interact with OAT1 in vitro. Thus, these latter compounds might represent physiological substrates of OAT1.

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Section: Methodsmentioning

confidence: 99%

Decreased Renal Organic Anion Secretion and Plasma Accumulation of Endogenous Organic Anions in OAT1 Knock-out Mice

Eraly

Vallon

Vaughn

et al. 2006

Journal of Biological Chemistry

217

246

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“…The opposite is described as well: alanine perfusion of the isolated rat kidney decreases net PAH secretion by 50% (MacDougall and Wiegmann, 1988). This interaction could reflect a shortage of energy rich substrates within the proximal tubular cell caused by increased PAH transport and followed by diminution of amino acid reabsorption.…”

Section: Discussionmentioning

confidence: 94%

Epidermal growth factor (EGF) increases the renal amino acid transport capacity in amino acid loaded rats

Fleck

Pertsch

1998

Amino Acids

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In anaesthetized adult female rats, the influence of epidermal growth factor (EGF) on renal amino acid handling was investigated in glutamine, arginine (both 50 mg/100 g b.wt. per hour), or alanine (90 mg/100 g b.wt. per hour) loaded animals. Continuous infusions of the three amino acids were followed by an increase in the fractional excretion (FE) of the administered amino acids as well as of the other endogenous amino acids. Under load conditions (alanine, arginine or glutamine), EGF pretreatment (8 micrograms/100 g b.wt. subcutaneously for 8 days, twice daily 8 a.m. and 4 p.m.) was followed by a stimulation of renal amino acid reabsorption. The increase in the fractional excretion of the administered amino acids was significantly lower than in non-EGF-treated rats. These changes in amino acid transport were connected with a significant reduction of GFR after EGF pretreatment (0.96 +/- 0.10 vs. 0.62 +/- 0.07 ml/min x 100 g b.wt.) and a distinct increase in sodium excretion (2.98 +/- 0.55 vs. 4.97 +/- 0.71 muval/100 g b.wt. x 20 min). After loading with p-aminohippurate (PAH; 200 mg/100 g b.wt.), PAH excretion in EGF rats was increased by about 20%, whereas urinary protein excretion was lower in EGF pretreated rats (control: 0.45 +/- 0.04 vs. EGF: 0.18 +/- 0.03 mg/100 g b.wt. x 20 min). The PAH load reduced amino acid reabsorption as a sign of overloading of renal tubular transport capacity, but in EGF pretreated animals the amino acid excretion was only slightly increased under these conditions. Furthermore, EGF pretreatment depressed normal kidney weight gain significantly (874 +/- 18 vs. 775 +/- 32 mg/100 g b.wt.). EGF can improve the renal tubular transport capacity, but, compared to well-known stimulators of renal transport like dexamethasone or triiodothyronine, its effect is only of a moderate degree.

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“…We have previously demonstrated intact proximal tubular organic acid secretion and the effects of secretory inhibition in this simple isolated kidney preparation (13). Attempts were then made to alter urate excretion with five different drugs.…”

Section: Discussionmentioning

confidence: 99%

“…Kidneys were isolated without interruption of flow as previously described ( 13). Standard perfusion medium contained, in mmol/liter: sodium 145, potassium 5.0, calcium 1.25, magnesium 1.18, bicarbonate 25, chloride 123, phosphate 1.20, sulfate 0.77, and glucose 5 with inulin 42 mg/dl and bovine serum albumin (Fraction V) 6.8 g/dl.…”

Section: Methodsmentioning

confidence: 99%

Urate Excretion by the Isolated Perfused Rat Kidney and Modification by Drugs

MacDougall¹,

Wiegmann²

1989

Experimental Biology and Medicine

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Urate excretion in the isolated perfused rat kidney was studied over a wide range of perfusate urate concentrations (13.9-376.8 wM). Fractional excretion of urate (FEumle) averaged 57.9 f 2.0% (range, 58.5-59.60/.), showed marked interanimal variability, but was not dependent on the perfusate-free urate concentration. In paired experiments, the effects of five drugs (probenecid, pyrazinoate, furosemide, salicylate, and oxonate) on F E . , , were evaluated. A low concentration of pyrazinoate (0.2 mM) decreased F E .

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Excretion of para‐aminohippurate in the isolated perfused rat kidney: net secretion and net reabsorption.

Cited by 11 publications

References 26 publications

Decreased Renal Organic Anion Secretion and Plasma Accumulation of Endogenous Organic Anions in OAT1 Knock-out Mice

Decreased Renal Organic Anion Secretion and Plasma Accumulation of Endogenous Organic Anions in OAT1 Knock-out Mice

Epidermal growth factor (EGF) increases the renal amino acid transport capacity in amino acid loaded rats

Urate Excretion by the Isolated Perfused Rat Kidney and Modification by Drugs

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