аЯрЁБс>ўџ 8:ўџџџ7џџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџџьЅС @№ПЧ)bjbj5*5* 8,W@W@€ џџџџџџˆ|||||||ддддL  ь88888888dffffff$RS јŠE|88888Š||88Я„„„8"|8|8d„8d„„||„8, я$ЁЮ&ШдZ„Pх0„K p K „||||K |„Ь88„88888ŠŠDдz д Dual Effect of Ochratoxin A (OTA) on the Renal Expression of Organic Anion Transporters Oat1 and Oat3 in Rats Zlender V, Ljubojevic M, Balen D, Breljak D, Brzica H, Fuchs R, Anzai N, Sabolic I Institute for Medical Research & Occupational Health, Zagreb, Croatia, and Pharmacology & Toxicology, Kyorin University School of Medicine, Tokyo, Japan OTA is an environmental mycotoxin that can impair human and animal health. In the kidney, OTA primarily targets epithelial cells in the proximal tubule (PT). PT is the major site of organic anion (OA) secretion via basolateral transporters Oat1 (Slc22a6) and Oat3 (Slc22a8). Earlier studies have shown that OTA inhibits the renal secretion of OA p-aminohyppurate (PAH), possibly by targeting the expression of Oat1 and Oat3, but this possibility has not been verified. To see if OTA affects the expression of these two Oats, we treated adult male Wistar rats with various doses of OTA (0, 50, 125, 250 & 500 Мg/kg b.w., p.o.) every 2nd day for 10 days, and determined: a) the expression of Oat1 and Oat3 proteins by Western blotting (WB) of total cell membranes isolated from the kidney and by immunocytochemistry (IC) in tissue cryosections, and b) the tissue expression of Oat1 and Oat2 mRNA by end-point PCR. The WB study of protein expression revealed a dual, dose-dependent effect of OTA; low doses (50-125 Мg/kg b.w.) increased the expression of Oat1 (~50%) and Oat3 (~300%), whereas high doses (250-500 Мg/kg b.w.) decreased the expression of Oat1 (~70%) but not Oat3 in respect to control. The IC data on staining intensity of both transporters in the PT completely matched the WB data. At the mRNA level the expression of Oat1 was unaffected by low OTA doses and downregulated by high OTA doses, whereas the expression of Oat3 was unaffected by any OTA dose. The mRNA expression of housekeeping gene GAPDH remained unchanged in all OTA-treated animals. We conclude that: a) low doses of OTA upregulate the expression%[\^`cegipqrs{‡ŸЇЉАВЛђхеШЛШеЎеШеЎеШЁ•†wk\kP\kAh :мh-IВCJaJmH sH h-IВCJaJmH sH h :мhBxCJaJmH sH hО]gCJaJmH sH hб6 hBxCJaJmH sH hб6 hО]gCJaJmH sH hY3MCJaJmH sH hBx5CJaJmH sH hr5CJaJmH sH hY3M5CJaJmH sH h,<—5CJaJmH sH h :мh<+˜5CJaJmH sH hl75CJaJmH sH h-I(5CJaJmH sH qrХЦ_ ` Ч)їїїїїїїїяя$a$gd-I($a$gd :м Ч)ўЛТФХЦШц  ^ _ ` a c h i | ‚ ‹ ‘ Љ ­ Б И єхжЩЙЌЙŸЌЙ’†w†h\hwhMhM>whb qhrCJaJmH sH hb qhќq,CJaJmH sH h‹ТCJaJmH sH hb qhUCqCJaJmH sH hb qh<+˜CJaJmH sH hY3MCJaJmH sH h†06CJaJmH sH h)Bƒ6CJaJmH sH hО]g6CJaJmH sH h :мhBx6CJaJmH sH hY3M6CJaJmH sH h)Bƒh†0CJaJmH sH h :мhBxCJaJmH sH hО]gCJaJmH sH И Й Р Я у ф ш ї ј ќ  7 B C O P S T ^ _ b f g q s z ƒ ётгёФИгтгЌёЌŽёЌёpёЌaRChb qh;%CJaJmH sH hb qhrCJaJmH sH hb qhг4ёCJaJmH sH hb qhOЖCJaJmH sH hb qhІCJaJmH sH hb qh$[ГCJaJmH sH hb qhk>,CJaJmH sH hY3MCJaJmH sH hїA2CJaJmH sH hb qhBxCJaJmH sH hb qh‘ECJaJmH sH hb qh<+˜CJaJmH sH hb qhќq,CJaJmH sH ƒ … ‡ З К У Ф Х а н ы §    + 3 4 5 6 7 ; d j y { Ž œ Ѕ К  , . ётгЧгИёИЌЧЧЌ‘‚sdёsёsётёUёU‚U‚Uё‚hb qh1ђCJaJmH sH hb qhz8.CJaJmH sH hb qhrCJaJmH sH hb qhпHоCJaJmH sH hРpCJaJmH sH hb qhІCJaJmH sH hY3MCJaJmH sH hb qhMKМCJaJmH sH hРPCJaJmH sH hb qh;%CJaJmH sH hb qh82йCJaJmH sH hb qhг4ёCJaJmH sH !. : @ € ˆ І Ў Ц и к м   : n p Š Т Ф ќ :`hj„ЎАёхёжЧИёЉёЉжёšЉŽsжdжXжdIЧhb qhеUCJaJmH sH h [CJaJmH sH hb qhи2_CJaJmH sH h,<—CJaJmH sH hb qh%ЇCJaJmH sH hY3MCJaJmH sH hb qhпHоCJaJmH sH hb qh41CJaJmH sH hb qh1ђCJaJmH sH hb qh82йCJaJmH sH hb qhh‚CJaJmH sH hТ\™CJaJmH sH hb qhг4ёCJaJmH sH АРТ *DFH^zŒ АЬЮю'.67?IQTётгтЧИЉЧтЉЧтš‹т‹pЧтЉЧšтš‹тpЉšЉpahb qhš.ЯCJaJmH sH hb qhЅ"lCJaJmH sH hРpCJaJmH sH hb qh aCJaJmH sH hb qh%ЇCJaJmH sH hb qhrCJaJmH sH hb qhЈ3CJaJmH sH hїA2CJaJmH sH hb qhr CJaJmH sH hb qhЕ%CJaJmH sH hb qhNq`CJaJmH sH !TWb‰Œ‘”ВХЦзSZdw‰ЎЕПСЪЯётгЧёЧёИЌётё‘‚ёsёgёXёLёLhРPCJaJmH sH hb qhбЦCJaJmH sH hPžCJaJmH sH hb qhьЃCJaJmH sH hb qh$[ГCJaJmH sH h$[ГCJaJmH sH hb qhЅ"lCJaJmH sH h‹ТCJaJmH sH hb qhš.ЯCJaJmH sH hїA2CJaJmH sH hb qh aCJaJmH sH hb qh?EиCJaJmH sH hb qhб]CJaJmH sH Яабсфя№ў((( ((,(3(K(L(Q(_(g(h(l((„(’(•(›(В(Ж(Ъ(Ы(Ю(3)ётгтФгЕГЄгт˜Œ˜ФгЄ€г€ФqbqЕS˜qФ€SФhb qhЅ"lCJaJmH sH hb qhЈ3CJaJmH sH hb qh<{цCJaJmH sH hїA2CJaJmH sH hY3MCJaJmH sH hн\дCJaJmH sH hb qhьЃCJaJmH sH Uhb qh?EиCJaJmH sH hb qhФ4CJaJmH sH hb qhЃmICJaJmH sH hb qhб]CJaJmH sH hb qhwаCJaJmH sH  of Oat1 and Oat3 proteins in the rat kidney, while high doses downregulate only the expression of Oat1, b) upregulation of Oat1 and Oat3 proteins is mRNA-unrelated, and seems to be post-transcriptional, c) previously observed inhibition of the renal PAH secretion in rodents may be related to the loss of Oat1 protein; and d) at lower OAT doses, upregulated Oat1 and Oat3 proteins may enhance OTA uptake and accelerate the development of nephrotoxicity. 3)6)>)?)T)t)u)~)Ѓ)Ї)Ч)ёхёжЪжОжёЏhb qhŠdйCJaJmH sH hЋCJaJmH sH h{jѕCJaJmH sH hb qhgTCJaJmH sH hїA2CJaJmH sH hb qhwаCJaJmH sH  6&P 1h:pX?А‚. 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