Oat1/3 restoration protects against renal damage after ischemic AKI.
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.
Medizinische Klinik und Poliklinik I, Abt. Nephrologie, Universitätsklinikum Würzburg, Würzburg, Germany; schneider_r@medizin.uni-wuerzburg.de.
R
R
Schneider
Medizinische Klinik und Poliklinik I, Abt. Nephrologie, Universitätsklinikum Würzburg, Würzburg, Germany;
M
M
Meusel
Medizinische Klinik und Poliklinik I, Abt. Nephrologie, Universitätsklinikum Würzburg, Würzburg, Germany;
B
B
Betz
Medizinische Klinik und Poliklinik I, Abt. Nephrologie, Universitätsklinikum Würzburg, Würzburg, Germany;
C
C
Held
Zentrum für Experimentelle Molekulare Medizin (ZEMM), Bayerische Julius-Maximilians Universität Würzburg, Würzburg, Germany;
K
K
Möller-Ehrlich
Nephropathologische Abteilung im Pathologischen Institut, Universitätsklinikum Erlangen, Erlangen, Germany.
M
M
Büttner-Herold
Medizinische Klinik und Poliklinik I, Abt. Nephrologie, Universitätsklinikum Würzburg, Würzburg, Germany;
C
C
Wanner
Julius-Bernstein-Institut für Physiologie, Universität Halle-Wittenberg, Halle, Germany; and.
M
M
Gekle
Klinik für Anästhesie und Operative Intensivmedizin, Universität Halle-Wittenberg, Halle, Germany;
C
C
Sauvant
D058186:Acute Kidney Injury / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D005919:Glomerular Filtration Rate / Q000187:drug effects; D007213:Indomethacin / Q000008:administration & dosage / Q000494:pharmacology; D007511:Ischemia / Q000188:drug therapy* / Q000378:metabolism; D007668:Kidney / Q000378:metabolism; D027362:Organic Anion Transport Protein 1 / Q000378:metabolism*; D029362:Organic Anion Transporters, Sodium-Independent / Q000378:metabolism*; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000378:metabolism
D027362:Organic Anion Transport Protein 1; D029362:Organic Anion Transporters, Sodium-Independent; C421043:Slc22a6 protein, rat; C114338:organic anion transport protein 3; D007213:Indomethacin
cyclooxygenase (COX); glomerular filtration rate (GFR), kidney cortex, monocytes/macrophages; ischemia; ischemic acute kidney injury (iAKI); renal organic anion transport; renal plasma flow (RPF); reperfusion