Downregulation of organic anion transporters in rat kidney under ischemia/reperfusion-induced acute [corrected] renal failure.
The effect of acute renal failure (ARF) induced by ischemia/reperfusion (I/R) of rat kidney on the expression of organic anion transporters (OATs) was examined. The level of serum indoxyl sulfate (IS), a uremic toxin and substrate of OATs in renal tubules, shows a marked increase with the progression of ARF. However, this increase was significantly attenuated by ingestion of cobalt. The level of mRNA and protein of both rOAT1 and rOAT3 were markedly depressed in the ischemic kidney. The uptake of p-aminohippuric acid (PAH) and estrone sulfate (ES) by renal slices of ischemic rats was significantly reduced compared to control rats. Renal slices taken from ischemic rats treated with cobalt displayed significantly elevated levels of ES uptake. Cobalt intake did not affect PAH uptake, indicating the functional restoration of rOAT3 but not rOAT1. The expression of Na(+)/K(+)-ATPase was markedly depressed in the ischemic kidney, suggesting that the inward Na(+) gradient in renal tubular cells had collapsed, thereby reducing the outward gradient of alpha-ketoglutarate, a driving force of both rOATs. The decreased expression of Na(+)/K(+)-ATPase was significantly restored by cobalt treatment. Our results suggest that the downregulation of renal rOAT1 and rOAT3 could be responsible for the increase in serum IS level of ischemic rats. Cobalt treatment has a significant protective effect on ischemia-induced ARF, being accompanied by the restoration of rOAT3 and/or Na(+)/K(+)-ATPase function.
Matsuzaki
T
T
Department of Pharmacy, Kumamoto University Hospital, Kumamoto, Japan.
Watanabe
H
H
Yoshitome
K
K
Morisaki
T
T
Hamada
A
A
Nonoguchi
H
H
Kohda
Y
Y
Tomita
K
K
Inui
K
K
Saito
H
H
D058186:Acute Kidney Injury / Q000209:etiology* / Q000378:metabolism* / Q000517:prevention & control; D000818:Animals; D003035:Cobalt / Q000627:therapeutic use; D015536:Down-Regulation / Q000502:physiology*; D004970:Estrone / Q000031:analogs & derivatives / Q000378:metabolism; D007200:Indican / Q000378:metabolism; D007668:Kidney / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D027362:Organic Anion Transport Protein 1 / Q000235:genetics / Q000378:metabolism*; D029362:Organic Anion Transporters, Sodium-Independent / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000150:complications* / Q000378:metabolism; D000254:Sodium-Potassium-Exchanging ATPase / Q000235:genetics / Q000378:metabolism; D014131:Trace Elements / Q000627:therapeutic use; D010130:p-Aminohippuric Acid / Q000378:metabolism
D027362:Organic Anion Transport Protein 1; D029362:Organic Anion Transporters, Sodium-Independent; D012333:RNA, Messenger; C421043:Slc22a6 protein, rat; D014131:Trace Elements; C114338:organic anion transport protein 3; D004970:Estrone; D003035:Cobalt; D000254:Sodium-Potassium-Exchanging ATPase; D007200:Indican; C017296:estrone sulfate; D010130:p-Aminohippuric Acid