Expression of proximal tubular
organic anion transporters Oat1 and Oat3 is reduced by
PGE2 after renal
ischemia and reperfusion (I/R) injury. We hypothesized that impaired expression of Oat1/3 is decisively involved in the deterioration of renal function after I/R injury. Therefore, we administered
probenecid, which blocks proximal tubular
indomethacin uptake, to abolish the
indomethacin-mediated restoration of Oat1/3 regulation and its effect on renal functional and morphological outcome. Ischemic
acute kidney injury (iAKI) was induced in rats by bilateral clamping of renal arteries for 45 min with 24-h follow-up. Low-dose
indomethacin (1 mg/kg) was given intraperitoneally (ip) at the end of
ischemia.
Probenecid (50 mg/kg) was administered
ip 20 min later.
Indomethacin restored the expression of Oat1/3, PAH net secretion, and
PGE2 clearance. Additionally,
indomethacin improved kidney function as measured by glomerular filtration rate (GFR), renal perfusion as determined by corrected PAH clearance, and morphology, whereas it reduced renal cortical apoptosis and
nitric oxide production. Notably,
indomethacin did not affect
inflammation parameters in the kidneys (e.g.,
monocyte chemoattractant protein-1, ED1+ cells). On the other hand,
probenecid blocked the
indomethacin-induced restoration of Oat1/3 and moreover abrogated all beneficial effects. Our study indicates that the beneficial effect of low-dose
indomethacin in iAKI is not due to its anti-inflammatory potency, but in contrast to its restoration of Oat1/3 expression and/or general renal function. Inhibition of proximal tubular
indomethacin uptake abrogates the beneficial effect of
indomethacin by resetting the PGE2-mediated Oat1/3 impairment, thus reestablishing renal damage. This provides evidence for a mechanistic effect of Oat1/3 in a new model of the induction of renal damage after iAKI.