Reduced expression of PPAR-β/δ limits the potential beneficial effects of GW0742 during septic shock in atherosclerotic swine

Abstract

Introduction The PPAR-beta/ agonist GW0742 was shown to attenuate cardiac dysfunction in murine septic shock [1] and renal ischemia/ reperfusion injury in diabetic rats [2]. Since these data originate from unresuscitated models, we investigated the effects of GW0742 during long-term, resuscitated porcine septic shock. In order to assess the role of pre-existing cardiovascular morbidity we used animals with familial hypercholesteremia (11.1 (7.4; 12.3) vs. 1.4 (1.3; 1.5) mmol/l in a healthy strain; P <0.001) and consecutive, diet-induced ubiquitous atherosclerosis resulting in coronary artery disease [3], reduced glomerular filtration rate (76 (60; 83) vs. 103 (79; 120) ml/minute in healthy swine; P = 0.004) and presence of chronic histological kidney injury. Methods Anesthetized and instrumented animals randomly received vehicle (n = 9) or GW0742 (n = 10; 0.03 mg/kg) at 6, 12, 18 hours after induction of fecal peritonitis [4]. Hydroxyethyl starch and noradrenaline were infused to maintain normotensive, hyperdynamic hemodynamics. Creatinine clearance was measured from 0 to 12 hours and from 12 to 24 hours of sepsis, respectively. Data are median (quartiles). Results GW0742 did not affect the noradrenaline infusion rate required to achieve target hemodynamics (0.57 (0.30; 3.83) vs. 0.56 (0.41; 0.91) mug/kg/minute; P = 0.775) nor the fall in creatinine clearance (GW0742: from 129 (114; 140) to 78 (55; 95) ml/minute, P = 0.002; vehicle: from 130 (91; 142) to 41(31; 84) ml/minute, P = 0.004; P = 0.967 and P = 0.191 between groups). Immune histochemistry analysis of kidney biopsies in sham-operated swine showed markedly reduced tissue expression of the PPAR-beta/ receptor in atherosclerotic swine (281 (277; 404) vs. 57 (53; 77)x103 densitometric units in healthy swine; P = 0.008). Conclusion Even early post-treatment with the PPAR-beta/ agonist GW0742 did not beneficially influence acute kidney injury during longterm, resuscitated fecal peritonitis-induced septic shock in swine with pre-existing impairment of kidney function and histological damage. The lacking beneficial effect of GW0742 was most likely due to the reduced expression of the PPAR-beta/ receptor.