Differential Effect of COX1 and COX2 Inhibitors on Renal Outcomes following Ischemic Acute Kidney Injury

Bischoff, Ariane; Bucher, Michael; Gekle, Michael; Sauvant, Christoph

doi:10.1159/000363251

Cited by 17 publications

(12 citation statements)

References 45 publications

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“…At least, this model represents a suitable tool for research on expression of hOAT1 and hOAT3. Consequently, we finally hypothesize that the beneficial effect of low dose indomethacin [19] or COX1-inhibiton [22] on expression and function of rOat1 (Slc22a6) and rOat3 (Slc22a8) detected in rats after renal I/R might also take place in humans. Even more important, the beneficial effect on renal outcome might also take place in humans.…”

Section: Cellular Physiology and Biochemistrymentioning

confidence: 92%

“…-Concentrations of H89 and butaprost were chosen according to our former study [28]. The same is true for SC560 and SC58125 [22]. U-73122 was applied according to the supplier (Tocris) giving an IC 50 below 5 µM.…”

Section: Methodsmentioning

confidence: 99%

“…Recently, we demonstrated I/R induced down regulation of (a) the transport of the prototypic organic anion fluorescein in OK cells, (b) the renal transport of organic anions and (c) the rOat1 and rOat3 regulation is most likely mediated by COX1 metabolites [15,21,22]. In kidney tissue, the expression of the G protein coupled E prostanoid receptors type 1 to 4 is well characterized.…”

Section: Fluorescein Transport Into Proximal Tubular Cell Line (Ok)mentioning

confidence: 99%

“…This effect was even more pronounced when selective COX1 inhibition was applied [22]. In the respective study, we gained serious evidence that I/R induced impairment of rOat1 and rOat3 expression is mediated by COX1 metabolites, whereas COX2 metabolites are most likely not involved.…”

Section: Introductionmentioning

confidence: 98%

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Regulation of Expression of Renal Organic Anion Transporters OAT1 and OAT3 in a Model of Ischemia/Reperfusion Injury

Preising

Schneider

Bucher

et al. 2015

Cell Physiol Biochem

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Background: Recently, we gained evidence that impairment of rOat1 and rOat3 expression induced by ischemic acute kidney injury (AKI) is mediated by COX metabolites and this suppression might be critically involved in renal damage. Methods: (i) Basolateral organic anion uptake into proximal tubular cells after model ischemia and reperfusion (I/R) was investigated by fluorescein uptake. The putative promoter sequences from hOAT1 (SLC22A6) and hOAT3 (SCL22A8) were cloned into a reporter plasmid, transfected into HEK cells and (ii) transcriptional activity was determined after model ischemia and reperfusion as a SEAP reporter gen assay. Inhibitors or antagonists were applied with the beginning of reperfusion. Results: By using inhibitors of PKA (H89) and PLC (U73122), antagonists of E prostanoid receptor type 2 (AH6809) and type 4 (L161,982), we gained evidence that I/R induced down regulation of organic anion transport is mediated by COX1 metabolites via E prostanoid receptor type 4. The latter signaling was confirmed by application of butaprost (EP2 agonist) or TCS2510 (EP4 agonist) to control cells. In brief, the latter signaling was verified for the transcriptional activity in the reporter gen assay established. Therein, selective inhibitors for COX1 (SC58125) and COX2 (SC560) were also applied. Conclusion: Our data show (a) that COX1 metabolites are involved in the regulation of renal organic anion transport(ers) after I/R via the EP4 receptor and (b) that this is due to transcriptional regulation of the respective transporters. As the promoter sequences cloned were of human origin and expressed in a human renal epithelial cell line we (c) hypothesize that the regulatory mechanisms described after I/R is meaningful for humans as well.

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Section: Cellular Physiology and Biochemistrymentioning

confidence: 92%

Section: Methodsmentioning

confidence: 99%

Section: Fluorescein Transport Into Proximal Tubular Cell Line (Ok)mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 98%

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Regulation of Expression of Renal Organic Anion Transporters OAT1 and OAT3 in a Model of Ischemia/Reperfusion Injury

Preising

Schneider

Bucher

et al. 2015

Cell Physiol Biochem

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“…Correction of PAH clearance for renal extraction was done in accordance to what we have published recently (2,3). Corrected PAH clearance as a measure for renal perfusion is calculated as follows: corrPAH…”

Section: Measurement Of Clearances Of Inulin (Gfr) and Pah (Rpf)mentioning

confidence: 99%

Oat1/3 restoration protects against renal damage after ischemic AKI

Schneider

Meusel

Betz

et al. 2015

American Journal of Physiology-Renal Physiology

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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.

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