title: Effects of sepiapterin infusion on renal oxygenation and early acute renal injury after suprarenal aortic clamping in rats.
abstract: Acute kidney injury (AKI) can occur after aortic clamping due to microvascular dysfunction leading to renal hypoxia. In this rat study, we have tested the hypothesis that the administration of the precursor of the nitric oxide synthase essential cofactor tetrahydrobiopterin (BH4) could restore renal oxygenation after ischemia reperfusion (I/R) and prevent AKI. We randomly distributed rats into 4 groups: sham group; ischemia-reperfusion group; I/R + sepiapterin, the precursor of BH4; and I/R + sepiapterin + methotrexate, an inhibitor of the pathway generating BH4 from sepiapterin. Cortical and outer medullary microvascular oxygen pressure, renal oxygen delivery, renal oxygen consumption were measured using dual-wavelength oxygen-dependent quenching phosphorescence techniques during ischemia and throughout 3 hours of reperfusion. Kidney injury was assessed using myeloperoxidase staining for leukocyte infiltration and urine neutrophil gelatinase-associated lipocalin levels. Ischemia reperfusion induced a drop in microvascular PO2 (P < 0.01 vs. Sham, both), which was prevented by the infusion of sepiapterin. Sepiapterin partially prevented the rise in renal oxygen extraction (P < 0.001 vs. I/R). Finally, treatment with sepiapterin prevented renal infiltration by inflammatory cells and decreased urine neutrophil gelatinase-associated lipocalin levels indicating a decrease of renal injury. These effects were blunted when adding methotrexate, except for myeloperoxidase. In conclusion, the administration of sepiapterin can prevent renal hypoxia and AKI after suprarenal aortic clamping in rats.
authors.affiliation: Department of Translational Physiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. m.legrand@libertysurf.fr
authors.forename: Matthieu
authors.initials: M
authors.lastname: Legrand
authors.forename: Asli
authors.initials: A
authors.lastname: Kandil
authors.forename: Didier
authors.initials: D
authors.lastname: Payen
authors.forename: Can
authors.initials: C
authors.lastname: Ince
mesh_terms: D058186:Acute Kidney Injury / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D000818:Animals; D001012:Aorta, Abdominal; D001708:Biopterins / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D007262:Infusions, Intravenous; D007668:Kidney / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism; D007677:Kidney Function Tests; D008297:Male; D008833:Microcirculation / Q000187:drug effects; D055806:Microvessels / Q000187:drug effects / Q000378:metabolism; D010101:Oxygen Consumption / Q000187:drug effects*; D011622:Pterins / Q000008:administration & dosage / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012079:Renal Circulation / Q000187:drug effects; D015427:Reperfusion Injury / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*
chemical_list: D011622:Pterins; D001708:Biopterins; C016727:sepiapterin; C003402:sapropterin