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Bohnert, B.N. ; González-Menéndez, I.* ; Dörffel, T.* ; Schneider, J.C.* ; Xiao, M.* ; Janessa, A.* ; Kalo, M.Z.* ; Fehrenbacher, B.* ; Schaller, M.* ; Casadei, N.* ; Amann, K.* ; Daniel, C.* ; Birkenfeld, A.L. ; Grahammer, F.* ; Izem, L.* ; Plow, E.F.* ; Quintanilla-Martinez, L.* ; Artunc, F.

Essential role of DNA-PKcs and plasminogen for the development of doxorubicin-induced glomerular injury in mice.

Dis. Model. Mech. 14:dmm049038 (2021)
Verlagsversion DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
Susceptibility to doxorubicin-induced nephropathy (DIN), a toxic model for the induction of proteinurie in mice, is related to the single nucleotide polymorphism (SNP) C6418T of the prkdc gene encoding for the DNA repair enzyme DNA-PKcs. In addition, plasminogen (plg) has been reported to play a role in glomerular damage. Here, we investigated the interdependence of both factors for the development of DIN. Genotyping confirmed the SNP of the prkdc gene in C57BL/6 (prkdcC6418/C6418) and 129S1/SvImJ (prkdcT6418/T6418) mice. Intercross of heterozygous 129SB6F1 mice led to 129SB6F2 hybrids with Mendelian inheritance of the SNP. After doxorubicin injection, only homozygous F2 mice with prkdcT6418/T6418 developed proteinuria. Genetic deficiency of plg (plg-/-) in otherwise susceptible 129S1/SvImJ mice led to resistance to DIN. Immunohistochemistry revealed glomerular binding of plg in plg+/+ mice after doxorubicin injection involving histone H2B as plg receptor. In doxorubicin resistant C57BL/6 mice, plg binding was absent. In conclusion, susceptibility to DIN in 129S1/SvImJ mice is determined by a hierarchical two hit process requiring the C6418T SNP in the prdkc gene and subsequent glomerular binding of plasminogen.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Dna-pkcs ; Doxorubicin ; Nephropathy ; Prkdc ; Plasminogen
ISSN (print) / ISBN 1754-8403
e-ISSN 1754-8411
Zeitschrift Disease Models and Mechanisms
Quellenangaben Band: 14, Heft: 9, Seiten: , Artikelnummer: dmm049038 Supplement: ,
Verlag Company of Biologists
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Diabetes Research and Metabolic Diseases (IDM)
Förderungen Deutsche Forschungsgemeinschaft