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Media type:
E-Article
Title:
Inhibition of COX-1 attenuates the formation of thromboxane A2and ameliorates the acute decrease in glomerular filtration rate in endotoxemic mice
Contributor:
Mederle, Katharina;
Meurer, Manuel;
Castrop, Hayo;
Höcherl, Klaus
imprint:
American Physiological Society, 2015
Published in:American Journal of Physiology-Renal Physiology
Description:
<jats:p>Thromboxane (Tx) A<jats:sub>2</jats:sub>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 TxA<jats:sub>2</jats:sub>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 TxB<jats:sub>2</jats:sub>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 TxB<jats:sub>2</jats:sub>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 TxB<jats:sub>2</jats:sub>. 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 TxB<jats:sub>2</jats:sub>levels. This study demonstrates that endotoxemia-induced TxA<jats:sub>2</jats:sub>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 TxA<jats:sub>2</jats:sub>in the development of AKI in response to LPS.</jats:p>