Elimination of organic anions in response to an early stage of renal ischemia-reperfusion in the rat: role of basolateral plasma membrane transporters and cortical renal blood flow.
OBJECTIVE
The knowledge of molecular mechanisms determining drug pharmacokinetics in pathological states is relevant for the development of new therapeutic approaches. This study was undertaken to evaluate the cortical renal blood flow (cRBF) and the renal protein expression of the organic anion transporters (OAT1 and OAT3) in association with the elimination of organic anions in an early stage of renal ischemia-reperfusion.


METHODS
Ischemic acute renal failure (ARF) was induced in adult male Wistar rats by occlusion of both renal pedicles during 60 min, followed by 60 min of reperfusion (ARF group). Pair-fed sham-operated rats served as controls. The renal protein expression of OAT1 and OAT3 was evaluated by immunohistochemistry techniques and by Western blotting in renal cortex homogenates and in basolateral plasma membranes. A pharmacokinetic study of p-aminohippurate (PAH, a prototypical organic anion) was performed. cRBF was determined using fluorescent microspheres.


RESULTS
ARF rats displayed a significant decrease in systemic clearance and in renal excretion of PAH. OAT1 and OAT3 protein abundance showed a statistically significant reduction both in homogenates and in basolateral plasma membranes from ARF rats. Immunohistochemical studies confirmed the changes in the cortical renal expression of these transporters. ARF animals also showed a decrease in cRBF.


CONCLUSIONS
The decrease in PAH elimination observed in an early stage of renal ischemia-reperfusion in male Wistar rats might be explained by the sum of the lower OAT1 and OAT3 expression in renal basolateral plasma membranes plus the decrease in cRBF. These findings might have significant implications in the development of novel pharmacological strategies to be applied in the initial stages of ischemic ARF.
Di Giusto
Gisela
G
Farmacología, Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario, CONICET, Rosario, Argentina.
Anzai
Naohiko
N
Endou
Hitoshi
H
Torres
Adriana M
AM
D058186:Acute Kidney Injury / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002462:Cell Membrane / Q000235:genetics / Q000502:physiology*; D007672:Kidney Cortex / Q000098:blood supply* / Q000378:metabolism*; D008297:Male; D026901:Membrane Transport Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D027361:Organic Anion Transporters / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D012079:Renal Circulation / Q000502:physiology*; D015427:Reperfusion Injury / Q000235:genetics / Q000378:metabolism*
D026901:Membrane Transport Proteins; D027361:Organic Anion Transporters