Indomethacin corrects alterations associated with ischemia/reperfusion in an in vitro proximal tubular model.
OBJECTIVE
Recent in vivo data indicate that indomethacin improves renal outcome after ischemia via improvement of renal cell survival and function. To examine direct effects of indomethacin on isolated proximal tubular cells, we investigated the influence of indomethacin on markers of ischemia/reperfusion (I/R) damage in an established in vitro model of ischemia and reperfusion.


METHODS
Ischemia was applied for 2 h followed by reperfusion for up to 48 h. Indomethacin was added at the beginning of reperfusion. Parameters were investigated after 6, 24 or 48 h of reperfusion.


RESULTS
Indomethacin diminished cell death by necrosis and apoptosis, release of prostaglandin E2, induction of I/R-induced protein, dedifferentiation or induction of inducible nitric oxide synthase. Moreover, indomethacin totally prevented the ischemia-induced inhibition of basolateral organic anion transport. Indomethacin did not affect ischemia-mediated induction of nuclear factor-kappaB or monocyte chemoattractant protein 1. Ischemia did not induce matrix protein synthesis.


CONCLUSIONS
We have shown that: (a) indomethacin applied after ischemia has a beneficial effect on proximal tubule cell survival after model ischemia and impairs changes of parameters characteristically induced by ischemia via direct action on proximal tubule cells; (b) the inflammatory response of proximal tubule cells was not affected by indomethacin, and (c) fibrosis does not take place after model ischemia in isolated proximal tubule cells.
Physiologisches Institut, Bayerische Julius-Maximilians Universität Würzburg, Würzburg, Deutschland. Sauvant_C@medizin.uni-wuerzburg.de
C
C
Sauvant
R
R
Schneider
H
H
Holzinger
S
S
Renker
C
C
Wanner
M
M
Gekle
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015415:Biomarkers; D002317:Cardiovascular Agents / Q000494:pharmacology; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000235:genetics; D015232:Dinoprostone / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D005109:Extracellular Matrix / Q000187:drug effects / Q000473:pathology; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology*; D007687:Kidney Tubules, Proximal / Q000166:cytology*; D016328:NF-kappa B / Q000378:metabolism; D009336:Necrosis; D052247:Nitric Oxide Synthase Type II / Q000235:genetics; D009893:Opossums; D027361:Organic Anion Transporters / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000473:pathology
D015415:Biomarkers; D002317:Cardiovascular Agents; C491766:Ccl2 protein, rat; D018932:Chemokine CCL2; D016328:NF-kappa B; D027361:Organic Anion Transporters; D012333:RNA, Messenger; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D015232:Dinoprostone; D007213:Indomethacin