title: Protective effect of nitric oxide in aristolochic acid-induced toxic acute kidney injury: an old friend with new assets.
abstract: Aristolochic acid (AA) nephropathy (AAN), a progressive tubulointerstitial injury of toxic origin, is characterized by early and transient acute tubular necrosis. This process has been demonstrated to be associated with reduced nitric oxide (NO) production, which can disrupt the regulation of renal function. In this study, we tested the hypothesis that L-arginine (L-Arg) supplementation could restore renal function and reduce renal injury after AA intoxication. C57BL/6 J male mice were randomly subjected to daily i.p. injection of either sterile saline solution or AA (2.5 mg kg(-1)) for 4 days. To determine whether AA-induced renal injuries were linked to reduced NO production, L-Arg, a substrate for NO synthase, was supplemented (5%) in drinking water. Mice intoxicated with AA exhibited features of rapid-onset acute kidney injury, including polyuria, significantly increased plasma creatinine concentrations, proteinuria and fractional excretion of sodium (P < 0.05), along with severe proximal tubular cell injury and increased NADPH oxidase 2 (Nox2)-derived oxidative stress (P < 0.05). This was associated with a significant reduction in NO bioavailability. L-Arg supplementation in AA-treated mice significantly increased NO bioavailability, which in turn improved renal function (creatininaemia, polyuria, proteinuria, fractional excreted sodium and N-acetyl-β-D-glucosaminidase enzymuria) and renal structure (tubular necrosis and tubular cell apoptosis). These changes were associated with significant reductions in Nox2 expression and in production of reactive oxygen species and with an increase in antioxidant concentrations. Our results demonstrate that preservation of NO bioavailability leads to renal protection in AA-induced acute kidney injury by reducing oxidative stress and maintaining renal function.
authors.affiliation: Molecular Physiology Research Unit-URPHYM, University of Namur (UNamur), B-5000, Namur, Belgium.|Laboratory of Experimental Nephrology, Faculty of Medicine, Université Libre de Bruxelles (ULB), B-1070, Brussels, Belgium.
authors.forename: Anne-Émilie
authors.initials: AÉ
authors.lastname: Declèves
authors.affiliation: Molecular Physiology Research Unit-URPHYM, University of Namur (UNamur), B-5000, Namur, Belgium.
authors.forename: Inès
authors.initials: I
authors.lastname: Jadot
authors.affiliation: Molecular Physiology Research Unit-URPHYM, University of Namur (UNamur), B-5000, Namur, Belgium.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Colombaro
authors.affiliation: Molecular Physiology Research Unit-URPHYM, University of Namur (UNamur), B-5000, Namur, Belgium.
authors.forename: Blanche
authors.initials: B
authors.lastname: Martin
authors.affiliation: Molecular Physiology Research Unit-URPHYM, University of Namur (UNamur), B-5000, Namur, Belgium.
authors.forename: Virginie
authors.initials: V
authors.lastname: Voisin
authors.affiliation: Laboratory of Experimental Nephrology, Faculty of Medicine, Université Libre de Bruxelles (ULB), B-1070, Brussels, Belgium.
authors.forename: Joëlle
authors.initials: J
authors.lastname: Nortier
authors.affiliation: Molecular Physiology Research Unit-URPHYM, University of Namur (UNamur), B-5000, Namur, Belgium.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Caron
mesh_terms: D058186:Acute Kidney Injury / Q000139:chemically induced* / Q000473:pathology / Q000517:prevention & control*; D000818:Animals; D001120:Arginine / Q000494:pharmacology; D034341:Aristolochic Acids; D003404:Creatinine / Q000097:blood; D006152:Cyclic GMP / Q000652:urine; D007668:Kidney / Q000473:pathology; D007687:Kidney Tubules, Proximal / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009569:Nitric Oxide / Q000627:therapeutic use*; D018384:Oxidative Stress / Q000187:drug effects; D011141:Polyuria / Q000139:chemically induced / Q000517:prevention & control; D011507:Proteinuria / Q000139:chemically induced / Q000517:prevention & control; D012964:Sodium / Q000652:urine; D013482:Superoxide Dismutase / Q000378:metabolism
chemical_list: D034341:Aristolochic Acids; D009569:Nitric Oxide; D001120:Arginine; D012964:Sodium; D003404:Creatinine; D013482:Superoxide Dismutase; D006152:Cyclic GMP