Expression of proximal tubular organic anion transporters rOat1/3 is diminished by prostaglandin E2 (PGE2) after renal ischemia and reperfusion. NSAID are thought to be contra indicated in ischemic acute kidney injury (iAKI) due to impairment of medullary blood flow. We setup a dose-response-study to determine beneficial or adverse effect of indomethacin.

iAKI was induced in rats by bilateral clamping of renal arteries for 45 min. Indomethacin was given i.p. as a single bolus (0.1, 1, 5, 10 in mg/kg) as soon as reperfusion started. Parameters were investigated after a reperfusion period of 24 h.

Indomethacin up to 5 mg/kg restored the expression of OAT1/3, PAH net secretion and PAH clearance in rats after iAKI. Moreover, GFR was improved. No effect of the mentioned doses was detected in sham treated animals, whereas 10 mg/kg indomethacin severely impaired GFR, PAH net secretion and PAH clearance in sham treated animals. Consequently, no beneficial effect was detectable at this particular dose. Thus, the effect of indomethacin is dose dependent with respect to all the parameters determined.

These data indicate that low dosed indomethacin accumulates in the proximal tubular cells and attenuates (COX1 induced) down-regulation of rOat1/3. Renal tubular damage is mitigated. At doses up to 5 mg/kg the amount is not sufficient to inhibit the generation of COX2 products which are known to positively influence perfusion. Above this particular dose COX2 is inhibited, which impairs renal medullary perfusion leading to renal injury.

Supported by DFG Grant SA 948/3-1 and Roux 22/23.