title: 5-Aminolevulinic acid combined with ferrous iron induces carbon monoxide generation in mouse kidneys and protects from renal ischemia-reperfusion injury.
abstract: Renal ischemia reperfusion injury (IRI) is a major factor responsible for acute renal failure. An intermediate in heme synthesis, 5-aminolevulinic acid (5-ALA) is fundamental in aerobic energy metabolism. Heme oxygenase (HO)-1 cleaves heme to form biliverdin, carbon monoxide (CO), and iron (Fe(2+)), which is used with 5-ALA. In the present study, we investigated the role of 5-ALA in the attenuation of acute renal IRI using a mouse model. Male Balb/c mice received 30 mg/kg 5-ALA with Fe(2+) 48, 24, and 2 h before IRI and were subsequently subjected to bilateral renal pedicle occlusion for 45 min. The endogenous CO concentration of the kidneys from the mice administered 5-ALA/Fe(2+) increased significantly, and the peak concentrations of serum creatinine and blood urea nitrogen decreased. 5-ALA/Fe(2+) treatments significantly decreased the tubular damage and number of apoptotic cells. IRI-induced renal thiobarbituric acid-reactive substance levels were also significantly decreased in the 5-ALA/Fe(2+) group. Furthermore, mRNA expression of HO-1, TNF-α, and interferon-γ was significantly increased after IRI. Levels of HO-1 were increased and levels of TNF-α and interferon-γ were decreased in the 5-ALA/Fe(2+)-pretreated renal parenchyma after IRI. F4/80 staining showed reduced macrophage infiltration, and TUNEL staining revealed that there were fewer interstitial apoptotic cells. These findings suggest that 5-ALA/Fe(2+) can protect the kidneys against IRI by reducing macrophage infiltration and decreasing renal cell apoptosis via the generation of CO.
authors.affiliation: Div. of Radiation Safety and Immune Tolerance, National Research Institute for Child Health and Development, 2-10-1 Okura, Setagaya-ku, Tokyo 157-8535, Japan. ri-k@ncchd.go.jp.
authors.forename: Jiangang
authors.initials: J
authors.lastname: Hou
authors.forename: Songjie
authors.initials: S
authors.lastname: Cai
authors.forename: Yuya
authors.initials: Y
authors.lastname: Kitajima
authors.forename: Masayuki
authors.initials: M
authors.lastname: Fujino
authors.forename: Hidenori
authors.initials: H
authors.lastname: Ito
authors.forename: Kiwamu
authors.initials: K
authors.lastname: Takahashi
authors.forename: Fuminori
authors.initials: F
authors.lastname: Abe
authors.forename: Tohru
authors.initials: T
authors.lastname: Tanaka
authors.forename: Qiang
authors.initials: Q
authors.lastname: Ding
authors.forename: Xiao-Kang
authors.initials: XK
authors.lastname: Li
mesh_terms: D058186:Acute Kidney Injury / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D000622:Aminolevulinic Acid / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D002248:Carbon Monoxide / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects / Q000235:genetics; D004353:Drug Evaluation, Preclinical; D004359:Drug Therapy, Combination; D005296:Ferrous Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D015427:Reperfusion Injury / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*
chemical_list: D005296:Ferrous Compounds; D012333:RNA, Messenger; D002248:Carbon Monoxide; D000622:Aminolevulinic Acid
keywords: 5-aminolevulinic acid; carbon monoxide; hemeoxygenase-1; ischemia-reperfusion injury; kidney; oxidative stress