Low doses of ochratoxin A upregulate the protein expression of organic anion transporters Oat1, Oat2, Oat3 and Oat5 in rat kidney cortex.
Mycotoxin ochratoxin A (OTA) is nephrotoxic in various animal species. In rodents, OTA intoxication impairs various proximal tubule (PT) functions, including secretion of p-aminohippurate (PAH), possibly via affecting the renal organic anion (OA) transporters (Oat). However, an effect of OTA on the activity/expression of specific Oats in the mammalian kidney has not been reported. In this work, male rats were gavaged various doses of OTA every 2nd day for 10 days, and in their kidneys we studied: tubule integrity by microscopy, abundance of basolateral (rOat1, rOat3) and brush-border (rOat2, rOat5) rOat proteins by immunochemical methods, and expression of rOats mRNA by RT-PCR. The OTA treatment caused: a) dose-dependent damage of the cells in S3 segments of medullary rays, b) dual effect upon rOats in PT: low doses (50-250 microg OTA/kg b.m.) upregulated the abundance of all rOats, while a high dose (500 microg OTA/kg b.m.) downregulated the abundance of rOat1, and c) unchanged mRNA expression for all rOats at low OTA doses, and its downregulation at high OTA dose. Changes in the expression of renal Oats were associated with enhanced OTA accumulation in tissue and excretion in urine, whereas the indicators of oxidative stress either remained unchanged (malondialdehyde, glutathione, 8-hydroxydeoxyguanosine) or became deranged (microtubules). While OTA accumulation and downregulation of rOats in the kidney are consistent with the previously reported impaired renal PAH secretion in rodents intoxicated with high OTA doses, the post-transcriptional upregulation of Oats at low OTA doses may contribute to OTA accumulation and development of nephrotoxicity.
Zlender
Vilim
V
Unit of Toxicology, Institute for Medical Research and Occupational Health, Zagreb, Croatia.
Breljak
Davorka
D
Ljubojević
Marija
M
Flajs
Dubravka
D
Balen
Daniela
D
Brzica
Hrvoje
H
Domijan
Ana-Marija
AM
Peraica
Maja
M
Fuchs
Radovan
R
Anzai
Naohiko
N
Sabolić
Ivan
I
D000818:Animals; D015153:Blotting, Western; D029382:Dicarboxylic Acid Transporters / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D004591:Electrophoresis, Polyacrylamide Gel; D007672:Kidney Cortex / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D007684:Kidney Tubules / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015227:Lipid Peroxidation / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009793:Ochratoxins / Q000493:pharmacokinetics / Q000633:toxicity* / Q000652:urine; D027362:Organic Anion Transport Protein 1 / Q000096:biosynthesis; D027361:Organic Anion Transporters / Q000096:biosynthesis*; D029362:Organic Anion Transporters, Sodium-Independent / Q000096:biosynthesis; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015854:Up-Regulation
D029382:Dicarboxylic Acid Transporters; D009793:Ochratoxins; D027362:Organic Anion Transport Protein 1; D027361:Organic Anion Transporters; D029362:Organic Anion Transporters, Sodium-Independent; C506835:Slc22a24 protein, rat; C421043:Slc22a6 protein, rat; C088800:Slc22a7 protein, rat; C114338:organic anion transport protein 3; C025589:ochratoxin A