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Inhibition of COX‐1 ameliorates endotoxemia‐induced fall in GFR in mice
Author(s) -
Mederle Katharina,
Castrop Hayo,
Schweda Frank,
Höcherl Klaus
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.705.3
Subject(s) - platelet , endocrinology , medicine , chemistry , lipopolysaccharide , thromboxane b2 , thromboxane , renal function , urine , thromboxane a2
In this study, we investigated the impact of COX‐1‐ and COX‐2‐derived prostanoids on lipopolysaccharide (LPS)‐induced decrease in glomerular filtration rate (GFR) in mice. Injection of LPS (3 mg/kg; i.p.; n=8) decreased GFR and the amount of thrombocytes to about 50% of basal values. Plasma, urine and renocortical tissue levels of TxB2 were increased about 10‐, 7‐ and 2‐fold in response to LPS, respectively. Pretreatment with the COX‐1 inhibitor SC‐560 (20 mg/kg) attenuated the LPS‐induced fall in GFR and in thrombocytes to about 75% of basal levels (n=8; p<0.01). Further, SC‐560 abolished the increase in plasma, urine and renocortical tissue levels of TxB2 in response to LPS. Pretreatment with the COX‐2 inhibitor SC‐236 (10 mg/kg) further enhanced the LPS‐induced fall in GFR to about 40% of basal values (n=6; p<0.05 vs. LPS). SC‐236 did not alter thrombocyte levels nor the LPS‐induced increase in plasma, urine and renocortical tissue levels of TxB2. Pretreatment with the P2Y12 antagonist Clopidogrel (n=6; 50 mg/kg × d; oral) for two days inhibited the LPS‐induced fall in thrombocytes, but did not attenuate the LPS‐induced decrease in GFR. This study demonstrates that endotoxemia‐induced decrease in GFR is mediated in part by COX‐1 derived prostanoids. Our data further suggest that vascular‐rather than thrombocyte‐derived thromboxane is responsible for the fall in GFR in response to LPS.