Background/Aims: 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-ĸB 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.

Feitoza CQ, Semedo P, Gonçalves GM, et al: Modulation of inflammatory response by selective inhibition of cyclooxygenase-1 and cyclooxygenase-2 in acute kidney injury. Inflamm Res 2010;59:167–175.
Tokuyama H, Hayashi K, Matsuda H, et al: Stenosis-dependent role of nitric oxide and prostaglandins in chronic renal ischemia. Am J Physiol Renal Physiol 2002;282:F859–F865.
Schneider R, Meusel M, Renker S, et al: Low-dose indomethacin after ischemic acute kidney injury prevents downregulation of Oat1/3 and improves renal outcome. Am J Physiol Renal Physiol 2009;297:F1614–F1621.
Sauvant C, Schneider R, Holzinger H, et al: Implementation of an in vitro model system for investigation of reperfusion damage after renal ischemia. Cell Physiol Biochem 2009;24:567–576.
Sauvant C, Holzinger H, Gekle M: The nephrotoxin ochratoxin A induces key parameters of chronic interstitial nephropathy in renal proximal tubular cells. Cell Physiol Biochem 2005;15:125–134.
Gekle M, Knaus P, Nielsen R, et al: TGF-β1 reduces megalin/cubilin-mediated endocytosis of albumin in proximal tubule-derived OK-cells. Nephrol Dial Transplant 2003;18(suppl 4):561.
Sauvant C, Holzinger H, Gekle M: Proximal tubular toxicity of ochratoxin A is amplified by simultaneous inhibition of the extracellular signal-regulated kinases 1/2. J Pharmacol Exp Ther 2005;313:234–241.
Sauvant C, Holzinger H, Gekle M: Prostaglandin E2 inhibits its own renal transport by downregulation of organic anion transporters rOAT1 and rOAT3. J Am Soc Nephrol 2006;17:46–53.
Jiang W, Prokopenko O, Wong L, et al: IRIP, a new ischemia/reperfusion-inducible protein that participates in the regulation of transporter activity. Mol Cell Biol 2005;25:6496–6508.
Abbate M, Brown D, Bonventre JV: Expression of NCAM recapitulates tubulogenic development in kidneys recovering from acute ischemia. Am J Physiol 1999;277:F454–F463.
Villanueva S, Cespedes C, Vio CP: Ischemic acute renal failure induces the expression of a wide range of nephrogenic proteins. Am J Physiol 2006;290:R861–R870.
Yoshida T, Kurella M, Beato F, et al: Monitoring changes in gene expression in renal ischemia-reperfusion in the rat. Kidney Int 2002;61:1646–1654.
Basile DP, Martin DR, Hammerman MR: Extracellular matrix-related genes in kidney after ischemic injury: potential role for TGF-β in repair. Am J Physiol 1998;275:F894–F903.
Feitoza CQ, Gonçalves GM, Semedo P, et al: Inhibition of COX-1 and -2 prior to renal ischemia/reperfusion injury decreases the development of fibrosis. Mol Med 2008;14:724–730.
Chatterjee PK, Patel NS, Kvale EO, et al: Inhibition of inducible nitric oxide synthase reduces renal ischemia/reperfusion injury. Kidney Int 2002;61:862–871.
Sanchez-Conde P, Rodríguez-López JM, Nicolás JL, et al: The comparative abilities of propofol and sevoflurane to modulate inflammation and oxidative stress in the kidney after aortic cross-clamping. Anesth Analg 2008;106:371–378.
Vos IH, Govers R, Gröne HJ, et al: NF-ĸB decoy oligodeoxynucleotides reduce monocyte infiltration in renal allografts. FASEB J 2000;14:815–822.
Sung FL, Zhu TY, Au-Yeung KK, et al: Enhanced MCP-1 expression during ischemia/reperfusion injury is mediated by oxidative stress and NF-ĸB. Kidney Int 2002;62:1160–1170.
Hamada T, Tsuchihashi S, Avanesyan A, et al: Cyclooxygenase-2 deficiency enhances Th2 immune responses and impairs neutrophil recruitment in hepatic ischemia/reperfusion injury. J Immunol 2008;180:1843–1853.
Candelario-Jalil E, González-Falcón A, García-Cabrera M, et al: Post-ischaemic treatment with the cyclooxygenase-2 inhibitor nimesulide reduces blood-brain barrier disruption and leukocyte infiltration following transient focal cerebral ischaemia in rats. J Neurochem 2007;100:1108–1120.
Knight S, Johns EJ: Effect of COX inhibitors and NO on renal hemodynamics following ischemia-reperfusion injury in normotensive and hypertensive rats. Am J Physiol Renal Physiol 2005;289:F1072–F1077.
Knight S, Johns EJ: Renal functional responses to ischaemia-reperfusion injury in normotensive and hypertensive rats following non-selective and selective cyclooxygenase inhibition with nitric oxide donation. Clin Exp Pharmacol Physiol 2008;35:11–16.
Guan Z, Gobé G, Willgoss D, Endre ZH: Renal endothelial dysfunction and impaired autoregulation after ischemia-reperfusion injury result from excess nitric oxide. Am J Physiol Renal Physiol 2006;291:F619–F628.
Abbate M, Zoja C, Rottoli D, et al: Proximal tubular cells promote fibrogenesis by TGF-β1-mediated induction of peritubular myofibroblasts. Kidney Int 2002;61:2066–2077.
Prakash J, de Borst MH, Lacombe M, et al: Inhibition of renal rho kinase attenuates ischemia/reperfusion-induced injury. J Am Soc Nephrol 2008;19:2086–2097.
Nony PA, Schnellmann RG: Mechanisms of renal cell repair and regeneration after acute renal failure. J Pharmacol Exp Ther 2003;304:905–912.
Ling H, Gengaro PE, Edelstein CL, et al: Effect of hypoxia on proximal tubules isolated from nitric oxide synthase knockout mice. Kidney Int 1998;53:1642–1646.
Du C, Guan Q, Diao H, et al: Nitric oxide induces apoptosis in renal tubular epithelial cells through activation of caspase-8. Am J Physiol Renal Physiol 2006;290:F1044–F1054.
Tunctan B, Yaghini FA, Estes A, Malik KU: Prostaglandins inhibit cytochrome P450 4A activity and contribute to endotoxin-induced hypotension in rats via nitric oxide production. Arch Pharm Res 2008;31:856–865.
Rieger JM, Shah AR, Gidday JM: Ischemia-reperfusion injury of retinal endothelium by cyclooxygenase- and xanthine oxidase-derived superoxide. Exp Eye Res 2002;74:493–501.
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