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• W2071537824 abstract "Renal excretion of organic anions such as para-aminohippurate is reduced during severe sepsis and following ischemia/reperfusion injury. In order to better define the pathophysiology of sepsis-associated renal tubular dysfunction we measured the effect of lipopolysaccharide on renocortical organic anion transporter (OAT) expression in the rat. Prostaglandin E2 (PGE2) downregulates OATs in vitro, therefore, we also evaluated the effect of the cyclooxygenase (COX)-2 inhibitor parecoxib on this process. Endotoxemia caused a time- and dose-dependent decrease of OAT1 and OAT3 expression that paralleled increased renocortical COX-2 expression and PGE2 formation. Pretreatment with parecoxib decreased endotoxin-stimulated PGE2 formation. Parecoxib attenuated OAT1 and OAT3 gene repression in the rat kidney following endotoxin treatment and during ischemia/reperfusion-induced acute renal injury. COX-2 inhibition improved the creatinine clearance in lipopolysaccharide-treated rats but not after ischemia/reperfusion-induced acute renal injury. The decreased clearance of para-aminohippurate in rats following endotoxin- or ischemia/reperfusion-induced renal injury was improved by parecoxib. Our findings show that COX-2 derived prostanoids downregulate OATs during lipopolysaccharide-induced acute renal injury. Renal excretion of organic anions such as para-aminohippurate is reduced during severe sepsis and following ischemia/reperfusion injury. In order to better define the pathophysiology of sepsis-associated renal tubular dysfunction we measured the effect of lipopolysaccharide on renocortical organic anion transporter (OAT) expression in the rat. Prostaglandin E2 (PGE2) downregulates OATs in vitro, therefore, we also evaluated the effect of the cyclooxygenase (COX)-2 inhibitor parecoxib on this process. Endotoxemia caused a time- and dose-dependent decrease of OAT1 and OAT3 expression that paralleled increased renocortical COX-2 expression and PGE2 formation. Pretreatment with parecoxib decreased endotoxin-stimulated PGE2 formation. Parecoxib attenuated OAT1 and OAT3 gene repression in the rat kidney following endotoxin treatment and during ischemia/reperfusion-induced acute renal injury. COX-2 inhibition improved the creatinine clearance in lipopolysaccharide-treated rats but not after ischemia/reperfusion-induced acute renal injury. The decreased clearance of para-aminohippurate in rats following endotoxin- or ischemia/reperfusion-induced renal injury was improved by parecoxib. Our findings show that COX-2 derived prostanoids downregulate OATs during lipopolysaccharide-induced acute renal injury. Sepsis and septic shock are important risk factors for acute renal failure (ARF), which is defined as the abrupt decline in glomerular filtration rate and tubular function.1.Thadhani R. Pascual M. Bonventre J.V. Acute renal failure.N Engl J Med. 1996; 334: 1448-1460Crossref PubMed Scopus (1434) Google Scholar The mortality rate of sepsis-related ARF is still high at 75%.2.Levy E.M. Viscoli C.M. Horwitz R.I. The effect of acute renal failure on mortality. A cohort analysis.JAMA. 1996; 275: 1489-1494Crossref PubMed Scopus (0) Google Scholar Therefore, the understanding of the pathogenesis of sepsis-related ARF is of critical importance. Several in vivo and in vitro studies have suggested that the reduction of glomerular filtration rate in sepsis is secondary to altered glomerular hemodynamics.3.De Vriese A.S. Prevention and treatment of acute renal failure in sepsis.J Am Soc Nephrol. 2003; 14: 792-805Crossref PubMed Scopus (80) Google Scholar However, the pathophysiology of sepsis-associated renal tubular dysfunction with altered renal handling of drugs has been poorly explained. The kidney excretes a large variety of drugs. Two principle processes are responsible for their renal elimination: glomerular filtration and proximal tubular secretion.4.Inui K.I. Masuda S. Saito H. Cellular and molecular aspects of drug transport in the kidney.Kidney Int. 2000; 58: 944-958Abstract Full Text Full Text PDF PubMed Scopus (380) Google Scholar The tubular secretion of organic anions, for example, needs cellular transport mechanisms. Organic anion transporters (OATs) are necessary for the uptake of organic anions from the peritubular plasma across the basolateral membrane into the proximal tubule cell in exchange for α-ketoglutarate.5.Anzai N. Kanai Y. Endou H. Organic anion transporter family: current knowledge.J Pharmacol Sci. 2006; 100: 411-426Crossref PubMed Scopus (179) Google Scholar Among the several OATs, the transporters OAT1 and OAT3 have been proposed to be responsible for this step.6.Burckhardt B.C. Burckhardt G. Transport of organic anions across the basolateral membrane of proximal tubule cells.Rev Physiol Biochem Pharmacol. 2003; 146: 95-158Crossref PubMed Scopus (245) Google Scholar In the past years, it became apparent that several chemically unrelated endogenous and exogenous compounds, like para-aminohippurate (PAH), cAMP, diuretics, and antibiotics are transported such as the OAT system.6.Burckhardt B.C. Burckhardt G. Transport of organic anions across the basolateral membrane of proximal tubule cells.Rev Physiol Biochem Pharmacol. 2003; 146: 95-158Crossref PubMed Scopus (245) Google Scholar In addition, prostaglandin E2 (PGE2) is secreted into the urine at substantial rates by the OAT system of renal proximal tubules, likely by OAT1 and OAT3.6.Burckhardt B.C. Burckhardt G. Transport of organic anions across the basolateral membrane of proximal tubule cells.Rev Physiol Biochem Pharmacol. 2003; 146: 95-158Crossref PubMed Scopus (245) Google Scholar, 7.Irish III, J.M. Secretion of prostaglandin E2 by rabbit proximal tubules.Am J Physiol. 1979; 237: F268-F273PubMed Google Scholar Recently, it has been demonstrated that PGE2 downregulates the expression OAT1 and OAT3 in vitro.8.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: 46-53Crossref PubMed Scopus (44) Google Scholar Moreover, it has been found that OATs are downregulated during ischemia/reperfusion (I/R)-induced ARF and ureteral obstruction,9.Matsuzaki T. Watanabe H. Yoshitome K. et al.Downregulation of organic anion transporters in rat kidney under ischemia/reperfusion-induced acute [corrected] renal failure.Kidney Int. 2007; 71: 539-547Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar, 10.Schneider R. Sauvant C. Betz B. et al.Downregulation of organic anion transporters OAT1 and OAT3 correlates with impaired secretion of para-aminohippurate after ischemic acute renal failure in rats.Am J Physiol Renal Physiol. 2007; 292: F1599-F1605Crossref PubMed Scopus (70) Google Scholar, 11.Villar S.R. Brandoni A. Anzai N. et al.Altered expression of rat renal cortical OAT1 and OAT3 in response to bilateral ureteral obstruction.Kidney Int. 2005; 68: 2704-2713Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar conditions under which renal cyclooxygensase (COX)-2 expression is increased.12.Chatterjee P.K. Brown P.A. Cuzzocrea S. et al.Calpain inhibitor-1 reduces renal ischemia/reperfusion injury in the rat.Kidney Int. 2001; 59: 2073-2083Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 13.Norregaard R. Jensen B.L. Li C. et al.COX-2 inhibition prevents downregulation of key renal water and sodium transport proteins in response to bilateral ureteral obstruction.Am J Physiol Renal Physiol. 2005; 289: F322-F333Crossref PubMed Scopus (84) Google Scholar Therefore, one may assume that the downregulation of OATs during ARF could be because of an increased formation of COX-2 derived PGE2. As renal COX-2 expression is increased in response to lipopolysaccharide (LPS),14.Ichitani Y. Holmberg K. Maunsbach A.B. et al.Cyclooxygenase-1 and cyclooxygenase-2 expression in rat kidney and adrenal gland after stimulation with systemic lipopolysaccharide: in situ hybridization and immunocytochemical studies.Cell Tissue Res. 2001; 303: 235-252Crossref PubMed Scopus (42) Google Scholar which is an experimental approach commonly used in examining the pathogenesis of sepsis, and because administration of LPS alters the renal handling of several drugs,15.Bergeron M.G. Bergeron Y. Influence of endotoxin on the intrarenal distribution of gentamicin, netilmicin, tobramycin, amikacin, and cephalothin.Antimicrob Agents Chemother. 1986; 29: 7-12Crossref PubMed Scopus (30) Google Scholar, 16.Ganzinger U. Haslberger A. Schiel H. et al.Influence of endotoxin on the distribution of cephalosporins in rabbits.J Antimicrob Chemother. 1986; 17: 785-793Crossref PubMed Scopus (14) Google Scholar, 17.Lugon J.R. Boim M.A. Ramos O.L. et al.Renal function and glomerular hemodynamics in male endotoxemic rats.Kidney Int. 1989; 36: 570-575Abstract Full Text PDF PubMed Scopus (72) Google Scholar, 18.Nadai M. Hasegawa T. Kato K. et al.Alterations in pharmacokinetics and protein binding behavior of cefazolin in endotoxemic rats.Antimicrob Agents Chemother. 1993; 37: 1781-1785Crossref PubMed Scopus (27) Google Scholar, 19.Nadai M. Hasegawa T. Kato K. et al.The disposition and renal handling of enprofylline in endotoxemic rats by bacterial lipopolysaccharide (LPS).Drug Metab Dispos. 1993; 21: 611-616PubMed Google Scholar, 20.Nadai M. Hasegawa T. Wang L. et al.Time-dependent changes in the pharmacokinetics and renal excretion of xanthine derivative enprofylline induced by bacterial endotoxin in rats.Biol Pharm Bull. 1995; 18: 1089-1093Crossref PubMed Scopus (10) Google Scholar, 21.Sun H. Frassetto L. Benet L.Z. Effects of renal failure on drug transport and metabolism.Pharmacol Ther. 2006; 109: 1-11Crossref PubMed Scopus (210) Google Scholar, 22.Tardif D. Beauchamp D. Bergeron M.G. Influence of endotoxin on the intracortical accumulation kinetics of gentamicin in rats.Antimicrob Agents Chemother. 1990; 34: 576-580Crossref PubMed Scopus (24) Google Scholar we investigated in this study the effect of LPS on the expression of OAT1 and OAT3 in the rat renal cortex. As we found that the LPS-induced downregulation of OATs is paralleled by an increased expression of renocortical COX-2 gene, we hypothesized that the downregulation of OATs during endotoxemia could be because of an enhanced formation of COX-2 derived PGE2 in the rat renal cortex. Therefore, we studied the effect of the COX-2 inhibitor parecoxib on LPS-induced downregulation of renocortical OATs and in addition on I/R-induced downregulation of OATs. Injection of LPS for 3 h did not alter mRNA expression of OAT1 and OAT3. However, treatment with LPS for 6 and 12 h decreased OAT1 and OAT3 mRNA expression in the rat renal cortex. OAT1 mRNA was downregulated to 56 and 42% of control levels 6 and 12 h after LPS injection, respectively. OAT3 mRNA levels decreased to 44 and 30% of control levels 6 and 12 h after LPS administration, respectively (Figure 1a). Injection of increasing doses of LPS (1, 3, and 10 mg/kg) caused a dose-dependent downregulation of OAT1 mRNA abundance to 67, 50, and 44% of control levels 12 h after LPS injection, respectively. OAT3 mRNA abundance also decreased dose dependent to 55, 40, and 29% of control values, respectively (Figure 1b). We further investigated the expression of OAT1 and OAT3 protein in basolateral membranes from the renal cortex of vehicle and LPS-treated animals and found that the expression of OAT1 and OAT3 protein was decreased in animals treated for 12 h with LPS (Figure 1c). OAT1 immunoreactivity was detected in proximal tubules of vehicle-treated rats and was clearly decreased in rats treated with LPS (Figure 2a–d).Figure 2Immunohistochemistry of OAT1 in the renal cortex. Vehicle (a, c) and LPS-treated rats (b, d). These figures are representative of typical samples from three rats. a, b ×200. c, d ×400.View Large Image Figure ViewerDownload (PPT) We further evaluated the effect of LPS on renocortical PGE2 formation and on the expression of the two COX-isoforms, because it has been suggested that PGE2 downregulates OATs in vitro.8.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: 46-53Crossref PubMed Scopus (44) Google Scholar Intravenous injection of LPS did not influence renocortical COX-1 gene expression (Figure 3a–c). Treatment with LPS (10 mg/kg) for 3, 6, and 12 h increased COX-2 mRNA expression in the rat renal cortex 3.1-, 3.8-, and 3.4-fold, respectively (Figure 3a). Injection of increasing doses of LPS (1, 3, and 10 mg/kg) caused a dose-dependent upregulation of COX-2 mRNA abundance to 190, 249, and 379% of control levels 12 h after LPS injection, respectively (Figure 3b). Twelve hours after LPS injection, renocortical COX-2 protein expression was increased about twofold of control levels (Figure 3c). The increase in COX-2 gene expression was paralleled by an increase in renocortical PGE2 concentration to 188% of baseline values (Figure 3d). To evaluate the role of COX-2 derived PGE2 for the downregulation of OATs during LPS treatment, we further investigated the effect of the COX-2 inhibitor parecoxib (20 mg/kg; i.p.). Parecoxib treatment decreased basal PGE2 tissue concentration to about 76% of control values and pretreatment with parecoxib for 1 h inhibited the LPS-induced rise in renocortical PGE2 formation (Figure 3d). Sole parecoxib treatment did not influence the expression of OAT1 and OAT3 (Figure 4a–d). In animals treated for 12 h with LPS in combination with parecoxib, mRNA expression of OAT1 substantially increased from 33 to 70% compared to treatment with LPS alone (Figure 4a). Furthermore, the combination of LPS with parecoxib attenuated the LPS-induced downregulation of OAT3 mRNA abundance from 43 to 70% (Figure 4b). Consistent with the mRNA expression levels, the decreased immunoreactivity of OAT1 and OAT3 in LPS-treated rats was markedly attenuated in response to additional parecoxib treatment (Figure 4c and d). Mean arterial pressure (MAP) decreased 12 h after LPS injection from 92±4 to 47±7 mm Hg. Sole parecoxib did not alter MAP, but attenuated the LPS-induced fall in MAP to about 72±6 mm Hg. Plasma urea levels and plasma creatinine levels increased 3.4- and 2.8-fold after injection of LPS, respectively. Parecoxib did not alter plasma creatinine levels, but attenuated the LPS-induced rise in plasma creatinine levels (Figure 5a). LPS injection decreased creatinine clearance from 0.85±0.07 to 0.36±0.04 ml/min. Parecoxib did not alter creatinine clearance, but attenuated the LPS-induced decrease in creatinine clearance (Figure 5b). PAH clearance was decreased 12 h after LPS injection. Parecoxib did not alter PAH clearance, but attenuated the LPS-induced fall in PAH clearance (Figure 5c). We further calculated tubular PAH secretion, which was not altered by sole treatment with parecoxib. However, parecoxib attenuated the LPS-induced fall in PAH net secretion (Figure 5d). MAP was not altered by I/R nor by additional or sole treatment with parecoxib after 12 h compared to the sham group. Ischemia for 30 min and reperfusion for 12 h decreased renocortical OAT1 and OAT3 expression. Sole parecoxib treatment did not influence the expression of OAT1 and OAT3 (Figure 6a–c), but attenuated the I/R-induced downregulation of OATs. The expression of OAT1 increased from 35 to 65% and the expression of OAT3 from 22 to 47% (Figure 6a–c). I/R clearly increased renocortical COX-2 protein expression as well as renocortical PGE2 tissue concentration (Figure 6d). Parecoxib did not influence plasma creatinine levels and did not alter the I/R-induced rise in plasma creatinine levels (Figure 7a). Parecoxib did not influence basal creatinine clearance and did not alter the I/R-induced decrease in creatinine clearance (Figure 7b). Parecoxib did not influence basal PAH clearance, but attenuated the I/R-induced fall in PAH clearance (Figure 7c). Parecoxib did not change basal tubular PAH secretion, but attenuated the I/R-induced fall in tubular PAH secretion (Figure 7d).Figure 7Effect of parecoxib (20 mg/kg) and ischemia/reperfusion (I/R) on plasma creatinine levels, creatinine clearance, p-aminohippurate (PAH) clearance and PAH secretion. (a) Plasma levels of creatinine, (b) creatinine clearance, (c) PAH clearance, and (d) of PAH secretion were determined 12 h after ischemia for 30 min. Values are mean±s.e.m. for six rats. *P<0.05 vs control. #P<0.05 vs I/R.View Large Image Figure ViewerDownload (PPT) In this study, we aimed to characterize the regulation of renocortical OATs during severe experimental inflammation. A bolus of 10 mg/kg LPS in our in vivo model caused a pronounced arterial hypotension associated with increased plasma creatinine levels, reduced creatinine clearance and reduced PAH clearance, indicating the validity of our model of severe experimental sepsis.23.Churchill P.C. Bidani A.K. Schwartz M.M. Renal effects of endotoxin in the male rat.Am J Physiol. 1987; 253: F244-F250PubMed Google Scholar, 24.Hocherl K. Dreher F. Kurtz A. et al.Cyclooxygenase-2 inhibition attenuates lipopolysaccharide-induced cardiovascular failure.Hypertension. 2002; 40: 947-953Crossref PubMed Scopus (63) Google Scholar In line with a previous observation, we found that injection of LPS does not alter renocortical COX-1 expression, but that LPS increases renocortical COX-2 mRNA and protein expression,14.Ichitani Y. Holmberg K. Maunsbach A.B. et al.Cyclooxygenase-1 and cyclooxygenase-2 expression in rat kidney and adrenal gland after stimulation with systemic lipopolysaccharide: in situ hybridization and immunocytochemical studies.Cell Tissue Res. 2001; 303: 235-252Crossref PubMed Scopus (42) Google Scholar suggesting that the increase of COX-2 in the renal cortex is a rapid process that is because of enhanced de novo synthesis of COX-2 protein rather than to impaired degradation. We further found that the increase in COX-2 is dose dependent and that the increase in renocortical COX-2 expression leads to an enhanced formation of renocortical PGE2. This finding fits with previous studies reporting a dose-dependent increase in renal tissue cytokine formation,25.Schmidt C. Hocherl K. Bucher M. Cytokine-mediated regulation of urea transporters during experimental endotoxemia.Am J Physiol Renal Physiol. 2007; 292: F1479-F1489Crossref PubMed Scopus (42) Google Scholar, 26.Schmidt C. Hocherl K. Schweda F. et al.Proinflammatory cytokines cause down-regulation of renal chloride entry pathways during sepsis.Crit Care Med. 2007; 35: 2110-2119Crossref PubMed Scopus (37) Google Scholar, 27.Schmidt C. Hocherl K. Schweda F. et al.Regulation of renal sodium transporters during severe inflammation.J Am Soc Nephrol. 2007; 18: 1072-1083Crossref PubMed Scopus (117) Google Scholar which are well-known stimuli for COX-2 expression during inflammation.28.Smith W.L. DeWitt D.L. Garavito R.M. Cyclooxygenases: structural, cellular, and molecular biology.Annu Rev Biochem. 2000; 69: 145-182Crossref PubMed Scopus (2335) Google Scholar We now found that LPS-induced ARF caused a time- and dose-dependent downregulation of OAT1 and OAT3 gene expression. Recently, it has been reported that PGE2 regulates OAT gene expression in vitro. It has been shown that PGE2 inhibits its own renal transport by downregulation of OAT1 and OAT3 gene expression in vitro.8.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: 46-53Crossref PubMed Scopus (44) Google Scholar In addition, it has been found that I/R downregulates the renal expression of OAT1 and OAT3.9.Matsuzaki T. Watanabe H. Yoshitome K. et al.Downregulation of organic anion transporters in rat kidney under ischemia/reperfusion-induced acute [corrected] renal failure.Kidney Int. 2007; 71: 539-547Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar, 10.Schneider R. Sauvant C. Betz B. et al.Downregulation of organic anion transporters OAT1 and OAT3 correlates with impaired secretion of para-aminohippurate after ischemic acute renal failure in rats.Am J Physiol Renal Physiol. 2007; 292: F1599-F1605Crossref PubMed Scopus (70) Google Scholar As COX-2 expression is increased under endotoxemia and I/R,12.Chatterjee P.K. Brown P.A. Cuzzocrea S. et al.Calpain inhibitor-1 reduces renal ischemia/reperfusion injury in the rat.Kidney Int. 2001; 59: 2073-2083Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar one might suggest that the downregulation of OATs during ARF could be because of an enhanced formation of COX-2 derived PGE2. We attempted to prove such a causal link between COX-2 expression and OAT1 and OAT3 expression by the use of the COX-2 inhibitor parecoxib. Parecoxib clearly attenuated the LPS-induced increase in renocortical PGE2 tissue concentration, suggesting that the LPS-induced rise in PGE2 concentration is COX-2 dependent. We now found that COX-2 inhibition attenuates the LPS-induced downregulation of OAT1 and OAT3 gene expression, suggesting that COX-2 derived PGE2 formation is of importance for the LPS-induced downregulation of OATs. To prove the functional consequence for the attenuated downregulation of OAT1 and OAT3 gene expression, we further investigated the renal clearance of PAH. Within the kidney, the organic anion PAH undergoes glomerular filtration and tubular secretion.29.Burckhardt G. Bahn A. Wolff N.A. Molecular physiology of renal p-aminohippurate secretion.News Physiol Sci. 2001; 16: 114-118PubMed Google Scholar With regard to the basolateral uptake of PAH from the blood into proximal tubule cells, especially OAT1 and OAT3 are of major importance and therefore for the tubular secretion of PAH.29.Burckhardt G. Bahn A. Wolff N.A. Molecular physiology of renal p-aminohippurate secretion.News Physiol Sci. 2001; 16: 114-118PubMed Google Scholar Confirming previous observations, COX-2 inhibition per se did not alter plasma creatinine concentration, creatinine clearance, and PAH clearance.30.Lopez-Parra M. Claria J. Planaguma A. et al.Cyclooxygenase-1 derived prostaglandins are involved in the maintenance of renal function in rats with cirrhosis and ascites.Br J Pharmacol. 2002; 135: 891-900Crossref PubMed Scopus (44) Google Scholar, 31.Patel N.S. Cuzzocrea S. Collino M. et al.The role of cycloxygenase-2 in the rodent kidney following ischaemia/reperfusion injury in vivo.Eur J Pharmacol. 2007; 562: 148-154Crossref PubMed Scopus (35) Google Scholar In line with data obtained for indomethacin, a nonselective COX inhibitor, we found that the LPS-induced decrease in PAH clearance was ameliorated by COX-2 inhibition, suggesting that the uptake of PAH and therefore the secretion of PAH is improved.17.Lugon J.R. Boim M.A. Ramos O.L. et al.Renal function and glomerular hemodynamics in male endotoxemic rats.Kidney Int. 1989; 36: 570-575Abstract Full Text PDF PubMed Scopus (72) Google Scholar However, inhibition of COX-2 also ameliorated the LPS-induced fall in creatinine clearance, probably because of the attenuation of LPS-induced hypotension.24.Hocherl K. Dreher F. Kurtz A. et al.Cyclooxygenase-2 inhibition attenuates lipopolysaccharide-induced cardiovascular failure.Hypertension. 2002; 40: 947-953Crossref PubMed Scopus (63) Google Scholar As the clearance of PAH depends on glomerular filtration rate and tubular secretion, the amelioration of PAH clearance by COX-2 inhibition could be because of the attenuation of OAT gene expression or because of the amelioration of glomerular filtration rate. To further specify the impact of COX-2 derived prostanoids for the downregulation of OATs and for the renal excretion of PAH, we further studied the effect of parecoxib on OAT gene expression and PAH clearance under I/R. In line with previous reports, we found that I/R downregulates OAT1 and OAT3 gene expression and that this downregulation is paralleled by a decrease in PAH clearance.9.Matsuzaki T. Watanabe H. Yoshitome K. et al.Downregulation of organic anion transporters in rat kidney under ischemia/reperfusion-induced acute [corrected] renal failure.Kidney Int. 2007; 71: 539-547Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar, 10.Schneider R. Sauvant C. Betz B. et al.Downregulation of organic anion transporters OAT1 and OAT3 correlates with impaired secretion of para-aminohippurate after ischemic acute renal failure in rats.Am J Physiol Renal Physiol. 2007; 292: F1599-F1605Crossref PubMed Scopus (70) Google Scholar We now found that COX-2 inhibition attenuates the downregulation of OAT1 and OAT3 gene expression in response to ischemia, suggesting that COX-2 derived prostanoids are of importance for this downregulation under I/R. To prove this assumption, we investigated the effect of I/R on renocortical COX-2 protein expression and on renocortical PGE2 concentration and found that COX-2 protein as well as PGE2 tissue concentration were increased under I/R. This finding fits very well with other studies reporting of an increased COX-2 expression under I/R.12.Chatterjee P.K. Brown P.A. Cuzzocrea S. et al.Calpain inhibitor-1 reduces renal ischemia/reperfusion injury in the rat.Kidney Int. 2001; 59: 2073-2083Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 32.Matsuyama M. Nakatani T. Hase T. et al.The expression of cyclooxygenases and lipoxygenases in renal ischemia–reperfusion injury.Transplant Proc. 2004; 36: 1939-1942Abstract Full Text Full Text PDF PubMed Scopus (22) Google Scholar, 33.Matsuyama M. Yoshimura R. Hase T. et al.Study of cyclooxygenase-2 in renal ischemia–reperfusion injury.Transplant Proc. 2005; 37: 370-372Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar, 34.Slimane M.A. Ferlicot S. Conti M. et al.Expression of cyclooxygenase 2 and prostaglandin E synthase after renal ischemia–reperfusion.Transplant Proc. 2002; 34: 2841-2842Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar In line with a previous report, COX-2 inhibition did not ameliorate creatinine clearance in response to I/R in our study.31.Patel N.S. Cuzzocrea S. Collino M. et al.The role of cycloxygenase-2 in the rodent kidney following ischaemia/reperfusion injury in vivo.Eur J Pharmacol. 2007; 562: 148-154Crossref PubMed Scopus (35) Google Scholar We also found that MAP was not altered after I/R.35.Di Giusto G. Anzai N. Endou H. et al.Elimination of organic anions in response to an early stage of renal ischemia–reperfusion in the rat: role of basolateral plasma membrane transporters and cortical renal blood flow.Pharmacology. 2008; 81: 127-136Crossref PubMed Scopus (35) Google Scholar The unchanged MAP under I/R may be therefore a good explanation, why additional parecoxib treatment did not alter the decrease in creatinine clearance under I/R. However, the COX-2 inhibitor parecoxib attenuated the decrease in PAH clearance. As parecoxib did not alter creatinine clearance during I/R, the amelioration of PAH clearance by parecoxib under I/R could be because of the attenuation of the downregulation of OAT gene expression. COX-2 inhibition did not completely abolish the downregulation of OATs during LPS-induced and I/R-induced ARF. Therefore, additional mechanisms have to be involved into the downregulation of OATs. As cAMP has been shown to increase the expression of at least human OAT3 gene and because adenylyl cyclases expression and therefore cAMP synthesis is decreased in response to LPS and I/R,36.Bae E.H. Lee K.S. Lee J. et al.Effects of {alpha}-lipoic acid on ischemia/reperfusion-induced renal dysfunction in rats.Am J Physiol Renal Physiol. 2008; 294: F272-F280Crossref PubMed Scopus (39) Google Scholar, 37.Ogasawara K. Terada T. Asaka J. et al.Human organic anion transporter 3 gene is regulated constitutively and inducibly via a cAMP-response element.J Pharmacol Exp Ther. 2006; 319: 317-322Crossref PubMed Scopus (29) Google Scholar, 38.Risoe P.K. Wang Y. Stuestol J.F. et al.Lipopolysaccharide attenuates mRNA levels of several adenylyl cyclase isoforms in vivo.Biochim Biophys Acta. 2007; 1772: 32-39Crossref PubMed Scopus (24) Google Scholar a decreased synthesis of cAMP might be a possible additional mechanism that could be responsible for the downregulation of renal OATs. In conclusion, we found that LPS-induced renocortical COX-2 gene expression and PGE2 formation is paralleled by a downregulation of OAT1 and OAT3 gene expression. Inhibition of COX-2 attenuated the LPS-induced decrease in OAT1 and OAT3 gene expression. Further, COX-2 inhibition attenuated the downregulation of renocortical OAT1 and OAT3 expression because of I/R. Moreover, COX-2 inhibition ameliorated LPS-induced renal dysfunction and attenuated LPS and ischemia-induced decrease of PAH transport. Therefore, this study contributes to our understanding about the mechanism of regulation and the pathophysiological implications of OATs under ARF. However, because COX-2 inhibition does not completely attenuate the downregulation of OATs during LPS-induced and I/R-induced ARF, additional mechanisms must be involved in the downregulation of renal OATs. All animal experiments were performed according to National Institutes of Health Guide for the Care and Use of Laboratory Animals. Male Sprague–Dawley rats (200–225 g) were obtained from Charles River (Sulzfeld, Germany). Rats received isotonic NaCl-solution (control) or LPS (Escherichia coli; Sigma-Aldrich Chemie GmbH, Taufkirchen, Germany; 10 mg/kg) intravenously and were killed 3, 6, or 12 h (n=6 per group) after LPS injection. In addition, rats (n=6 per group) treated with parecoxib (20 mg/kg; i.p.) alone or parecoxib 1 h before LPS injection were investigated. The doses of LPS and of parecoxib were chosen from the literature.31.Patel N.S. Cuzzocrea S. Collino M. et al.The role of cycloxygenase-2 in the rodent kidney following ischaemia/reperfusion injury in vivo.Eur J Pharmacol. 2007; 562: 148-154Crossref PubMed Scopus (35) Google Scholar, 39.Bucher M. Ittner K.P. Hobbhahn J. et al.Downregulation of angiotensin II type 1 receptors during sepsis.Hypertension. 2001; 38: 177-182Crossref PubMed Scopus (81) Google Scholar Rats were anesthetized with sevoflurane, using a Trajan 808 (Dräger, Lübeck, Germany). For induction of renal I/R injury, renal arteries of rats (n=6 per group) were totally occluded for 30 min with microaneurysm clamps followed by reperfusion for 12 h. In sham controls, renal arteries were only touched with a forceps. The right femoral artery was cannulated for continuous monitoring of MAP (Siemens SC 9000, Munich, Germany). The left femoral vein was cannulated for maintenance infusion and the bladder for collecting urine. Clearance of PAH, plasma levels of creatinine, and creatinine clearance were determined as described previously.40.Hocherl K. Hensel C. Ulbricht B. et al.Everolimus treatment downregulates renocortical cyclooxygenase-2 expression in the rat kidney.Br J Pharmacol. 2005; 145: 1112-1122Crossref PubMed Scopus (5) Google Scholar, 41.Schneider R. Raff U. Vornberger N. et al.-arginine counteracts nitric oxide deficiency and improves the recovery phase of ischemic acute renal failure in rats.Kidney Int. 2003; 64: 216-225Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar Real-time PCR was performed in a LightCycler (Roche, Mannheim, Germany) as described previously.42.Matzdorf C. Kurtz A. Hocherl K. COX-2 activity determines the level of renin expression but is dispensable for acute upregulation of renin expression in rat kidneys.Am J Physiol Renal Physiol. 2007; 292: F1782-F1790Crossref PubMed Scopus (37) Google Scholar The primer sets were chosen from the literature.10.Schneider R. Sauvant C. Betz B. et al.Downregulation of organic anion transporters OAT1 and OAT3 correlates with impaired secretion of para-aminohippurate after ischemic acute renal failure in rats.Am J Physiol Renal Physiol. 2007; 292: F1599-F1605Crossref PubMed Scopus (70) Google Scholar For each sample, the ratio of the amount of mRNA to β-actin mRNA was calculated. Protein preparation and immunoblotting were performed as described previously.43.Hocherl K. Kees F. Kramer B.K. et al.Cyclosporine A attenuates the natriuretic action of loop diuretics by inhibition of renal COX-2 expression.Kidney Int. 2004; 65: 2071-2080Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar Antibodies against OAT1 and OAT3 (Alpha Diagnostics, San Antonio, TX, USA; 1:500) and COX-1 and COX-2 (Cayman Chemical, Ann Arbor, MI, USA; 1:1,000) were used. The preparation of basolateral membranes was performed as described in the literature by others.11.Villar S.R. Brandoni A. Anzai N. et al.Altered expression of rat renal cortical OAT1 and OAT3 in response to bilateral ureteral obstruction.Kidney Int. 2005; 68: 2704-2713Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar OAT1 and OAT3 were detected as approximately 60- and 110-kDa bands, respectively, as previously reported.10.Schneider R. Sauvant C. Betz B. et al.Downregulation of organic anion transporters OAT1 and OAT3 correlates with impaired secretion of para-aminohippurate after ischemic acute renal failure in rats.Am J Physiol Renal Physiol. 2007; 292: F1599-F1605Crossref PubMed Scopus (70) Google Scholar, 44.Ljubojevic M. Herak-Kramberger C.M. Hagos Y. et al.Rat renal cortical OAT1 and OAT3 exhibit gender differences determined by both androgen stimulation and estrogen inhibition.Am J Physiol Renal Physiol. 2004; 287: F124-F138Crossref PubMed Scopus (134) Google Scholar, 45.Torres A.M. Mac Laughlin M. Muller A. et al.Altered renal elimination of organic anions in rats with chronic renal failure.Biochim Biophys Acta. 2005; 1740: 29-37Crossref PubMed Scopus (46) Google Scholar, 46.Zhang R. Yang X. Li J. et al.Upregulation of rat renal cortical organic anion transporter (OAT1 and OAT3) expression in response to ischemia/reperfusion injury.Am J Nephrol. 2008; 28: 772-783Crossref PubMed Scopus (13) Google Scholar The kidneys were perfusion fixed with 4% paraformaldehyde and processed as described.47.Sauter A. Machura K. Neubauer B. et al.Development of renin expression in the mouse kidney.Kidney Int. 2008; 73: 43-51Abstract Full Text Full Text PDF PubMed Scopus (56) Google Scholar Immunolabeling was performed on 5-μm paraffin sections. Sections were incubated with a commercial available antibody against OAT1 (Alpha Diagnostics; 1:200) overnight at 4 °C. After several washing steps and blocking with phenylhydrazine, the sections were incubated with a rhodamine (tetramethyl rhodamine isothiocyanate)-conjugated fluorescent antibody (Dianova, Hamburg, Germany) for 2 h and mounted with glycergel (DakoCytomation, Glostrup, Denmark). Renocortical tissue levels of PGE2 were assayed as described previously.48.Hocherl K. Wolf K. Castrop H. et al.Renocortical expression of renin and of cyclooxygenase-2 in response to angiotensin II AT1 receptor blockade is closely coordinated but not causally linked.Pflugers Arch. 2001; 442: 821-827Crossref PubMed Scopus (20) Google Scholar Data were analyzed by analysis of variance with multiple comparisons followed by the t-test with Bonferroni adjustment. P<0.05 was considered significant. All the authors declared no competing interests. This study was financially supported by grants from the Deutsche Forschungsgemeinschaft (DFG, SFB 699) to KH and MB and by a grant of the Klinikum der Universität Regensburg (Reform) to CS. The technical assistance provided by Ramona Mogge and Maria Hirblinger is thankfully acknowledged." @default.
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• W2071537824 title "COX-2 inhibition attenuates endotoxin-induced downregulation of organic anion transporters in the rat renal cortex" @default.
• W2071537824 cites W1588849194 @default.
• W2071537824 cites W1963820674 @default.
• W2071537824 cites W1969587607 @default.
• W2071537824 cites W1976423162 @default.
• W2071537824 cites W1976517810 @default.
• W2071537824 cites W1983331685 @default.
• W2071537824 cites W1987937159 @default.
• W2071537824 cites W1992983589 @default.
• W2071537824 cites W1995626493 @default.
• W2071537824 cites W1999224438 @default.
• W2071537824 cites W2000516081 @default.
• W2071537824 cites W2003374359 @default.
• W2071537824 cites W2011100509 @default.
• W2071537824 cites W2027877078 @default.
• W2071537824 cites W2029723446 @default.
• W2071537824 cites W2033568319 @default.
• W2071537824 cites W2033921836 @default.
• W2071537824 cites W2035599956 @default.
• W2071537824 cites W2040715439 @default.
• W2071537824 cites W2043912604 @default.
• W2071537824 cites W2047138625 @default.
• W2071537824 cites W2048930760 @default.
• W2071537824 cites W2059429180 @default.
• W2071537824 cites W2064492065 @default.
• W2071537824 cites W2066015246 @default.
• W2071537824 cites W2073650307 @default.
• W2071537824 cites W2077149526 @default.
• W2071537824 cites W2082936029 @default.
• W2071537824 cites W2090969152 @default.
• W2071537824 cites W2106847296 @default.
• W2071537824 cites W2108868210 @default.
• W2071537824 cites W2109327979 @default.
• W2071537824 cites W2111210621 @default.
• W2071537824 cites W2123233116 @default.
• W2071537824 cites W2126853519 @default.
• W2071537824 cites W2130846098 @default.
• W2071537824 cites W2153201315 @default.
• W2071537824 cites W2156578117 @default.
• W2071537824 cites W2157795412 @default.
• W2071537824 cites W2159485385 @default.
• W2071537824 cites W2160277272 @default.
• W2071537824 cites W2166344923 @default.
• W2071537824 cites W2320208044 @default.
• W2071537824 cites W4236514815 @default.
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