The role of the proximal tubule in ochratoxin A nephrotoxicity in vivo: toxodynamic and toxokinetic aspects.
The proximal tubule of the kidney is regarded the main intrarenal target of the nephrotoxin Ochratoxin A (OTA). To gain further insight into the importance of the proximal tubule we investigated renal p-aminohippurate (PAH), inorganic phosphate (P), amino acid (AA) and OTA handling in male Wistar rats. The acute application of OTA (1.2 mg/kg) did not affect the renal handling of any of the substances investigated in contrast to the acute effect of OTA on 'postproximal' parts of the nephron. Application of OTA (0.5 mg/(kg.day)) over 6 days resulted in a dramatic decrease of the transport maximum of PAH (reduction to 15% of control) and to an increase of the apparent affinity of PAH to the organic anion transporter. Absolute excretion of P was not increased, whereas--due to the reduced GFR--the fractional excretion (FE) increased (to 180% of control). FE of the AA was not affected by OTA. Free-flow micropuncture experiments performed in L-homoarginine-loaded rats--to unmask possible small alterations of the amino acid transport kinetics--revealed that the proximal tubular transport of amino acids is not impaired by OTA. Subchronic exposure of the animals to OTA reduced the excretion of the mycotoxin itself to about 15% of controls. We conclude that the proximal tubule is not the main but one important intrarenal target of subchronically applied OTA. Furthermore, the action of OTA on the proximal tubule leads to decreased capacity to eliminate OTA possibly resulting in a self-enhancing effect.
Gekle
M
M
Department of Physiology, University of Würzburg, FRG.
Silbernagl
S
S
D000596:Amino Acids / Q000378:metabolism / Q000652:urine; D000818:Animals; D001692:Biological Transport; D005919:Glomerular Filtration Rate / Q000187:drug effects; D007687:Kidney Tubules, Proximal / Q000187:drug effects*; D008297:Male; D009793:Ochratoxins / Q000493:pharmacokinetics / Q000633:toxicity*; D010710:Phosphates / Q000378:metabolism / Q000652:urine; D051381:Rats; D017208:Rats, Wistar; D010130:p-Aminohippuric Acid / Q000378:metabolism
D000596:Amino Acids; D009793:Ochratoxins; D010710:Phosphates; C025589:ochratoxin A; D010130:p-Aminohippuric Acid