title: Unilateral ureteral obstruction induces DNA repair by APE1.
abstract: Ureteral obstruction is associated with oxidative stress and the development of fibrosis of the kidney parenchyma. Apurinic/apyrimidinic endonuclease (APE1) is an essential DNA repair enzyme for repair of oxidative DNA lesions and regulates several transcription factors. The aim of the present study was to investigate whether APE1 is regulated by acute (24 h) and chronic (7 days) unilateral ureteral obstruction (UUO). APE1 was expressed in essentially all kidney cells with the strongest expression in proximal tubuli. After 24 h of UUO, APE1 mRNA was induced in the cortex, inner stripe of the outer medulla (ISOM), and inner medulla (IM). In contrast, the APE1 protein level was not regulated in the IM and ISOM and only slightly increased in the cortex. APE1 DNA repair activity was not significantly changed. A different pattern of regulation was observed after 7 days of UUO, with an increase of the APE1 mRNA level in the cortex but not in the ISOM and IM. The APE1 protein level in the cortex, ISOM, and IM increased significantly. Importantly, we observed a significant increase in APE1 DNA repair activity in the cortex and IM. To confirm our model, we investigated heme oxygenase-1, collagen type I, fibronectin I, and α-smooth muscle actin levels. In vitro, we found the transcriptional regulatory activity of APE1 to be involved in the upregulation of the profibrotic factor connective tissue growth factor. In summary, APE1 is regulated at different levels after acute and chronic UUO. Thus, our results suggest that DNA repair activity is regulated in response to progressive (7 days) obstruction and that APE1 potentially could play a role in the development of fibrosis in kidney disease.
authors.affiliation: Department of Clinical Medicine, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Maria D
authors.initials: MD
authors.lastname: Aamann
authors.affiliation: Department of Clinical Medicine, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Rikke
authors.initials: R
authors.lastname: Nørregaard
authors.affiliation: Department of Clinical Medicine, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Marie Louise Vindvad
authors.initials: ML
authors.lastname: Kristensen
authors.affiliation: Danish Center for Molecular Gerontology and Danish Aging Research Center, Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark; and.
authors.forename: Tinna
authors.initials: T
authors.lastname: Stevnsner
authors.affiliation: Department of Clinical Medicine, Aarhus University Hospital, Aarhus, Denmark; JF@clin.au.dk.|Department of Clinical Physiology and Molecular Imaging, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Jørgen
authors.initials: J
authors.lastname: Frøkiær
mesh_terms: D000818:Animals; D024042:Collagen Type I / Q000378:metabolism; D004260:DNA Repair; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D005353:Fibronectins / Q000378:metabolism; D005355:Fibrosis / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation; D051547:Heme Oxygenase-1 / Q000378:metabolism; D007668:Kidney / Q000378:metabolism* / Q000473:pathology; D008297:Male; D018384:Oxidative Stress / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D014517:Ureteral Obstruction / Q000378:metabolism* / Q000473:pathology
chemical_list: D024042:Collagen Type I; D005353:Fibronectins; D051547:Heme Oxygenase-1; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase
keywords: DNA repair; apurinic/apyrimidinic endonuclease I; fibrosis; kidney; obstructive nephropathy; unilateral ureteral obstruction