title: Inhibition of COX-1 attenuates the formation of thromboxane A2 and ameliorates the acute decrease in glomerular filtration rate in endotoxemic mice.
abstract: Thromboxane (Tx) A2 has been suggested to be involved in the development of sepsis-induced acute kidney injury (AKI). Therefore, we investigated the impact of cyclooxygenase (COX)-1 and COX-2 activity on lipopolysaccharide (LPS)-induced renal TxA2 formation, and on endotoxemia-induced AKI in mice. Injection of LPS (3 mg/kg ip) decreased glomerular filtration rate (GFR) and the amount of thrombocytes to ∼50% of basal values after 4 h. Plasma and renocortical tissue levels of TxB2 were increased ∼10- and 1.7-fold in response to LPS, respectively. The COX-1 inhibitor SC-560 attenuated the LPS-induced fall in GFR and in platelet count to ∼75% of basal levels. Furthermore, SC-560 abolished the increase in plasma and renocortical tissue levels of TxB2 in response to LPS. The COX-2 inhibitor SC-236 further enhanced the LPS-induced decrease in GFR to ∼40% of basal values. SC-236 did not alter thrombocyte levels nor the LPS-induced increase in plasma and renocortical tissue levels of TxB2. Pretreatment with clopidogrel inhibited the LPS-induced drop in thrombocyte count, but did not attenuate the LPS-induced decrease in GFR and the increase in plasma TxB2 levels. This study demonstrates that endotoxemia-induced TxA2 formation depends on the activity of COX-1. Our study further indicates that the COX-1 inhibitor SC-560 has a protective effect on the decrease in renal function in response to endotoxin. Therefore, our data support a role for TxA2 in the development of AKI in response to LPS.
authors.affiliation: Institute of Physiology, University of Regensburg, Regensburg, Germany; and.
authors.forename: Katharina
authors.initials: K
authors.lastname: Mederle
authors.affiliation: Institute of Experimental and Clinical Pharmacology and Toxicology, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany.
authors.forename: Manuel
authors.initials: M
authors.lastname: Meurer
authors.affiliation: Institute of Physiology, University of Regensburg, Regensburg, Germany; and.
authors.forename: Hayo
authors.initials: H
authors.lastname: Castrop
authors.affiliation: Institute of Experimental and Clinical Pharmacology and Toxicology, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany klaus.hoecherl@fau.de.
authors.forename: Klaus
authors.initials: K
authors.lastname: Höcherl
mesh_terms: D058186:Acute Kidney Injury / Q000201:enzymology / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D000818:Animals; D001792:Blood Platelets / Q000187:drug effects / Q000201:enzymology; D051545:Cyclooxygenase 1 / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D004195:Disease Models, Animal; D015536:Down-Regulation; D019446:Endotoxemia / Q000139:chemically induced / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D004731:Endotoxins; D005919:Glomerular Filtration Rate / Q000187:drug effects*; D007668:Kidney / Q000187:drug effects* / Q000201:enzymology / Q000503:physiopathology; D008297:Male; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008810:Mice, Inbred C57BL; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D013928:Thromboxane A2 / Q000378:metabolism*; D013997:Time Factors
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D004731:Endotoxins; D008565:Membrane Proteins; D010975:Platelet Aggregation Inhibitors; D011720:Pyrazoles; C115461:SC 560; D013928:Thromboxane A2; C044101:endotoxin, Escherichia coli; D051545:Cyclooxygenase 1; C496512:Ptgs1 protein, mouse
keywords: acute kidney injury; cyclooxygenase; inflammation; lipopolysaccharide; thromboxane