{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,19]],"date-time":"2026-03-19T23:15:59Z","timestamp":1773962159094,"version":"3.50.1"},"reference-count":35,"publisher":"The Company of Biologists","issue":"9","license":[{"start":{"date-parts":[[2021,9,15]],"date-time":"2021-09-15T00:00:00Z","timestamp":1631664000000},"content-version":"vor","delay-in-days":14,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"crossref","award":["AR 1092\/2-2"],"award-info":[{"award-number":["AR 1092\/2-2"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["2 P01 HL076491"],"award-info":[{"award-number":["2 P01 HL076491"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,9,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n               <jats:p>Susceptibility to doxorubicin-induced nephropathy (DIN), a toxic model for the induction of proteinuria 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\u2212\/\u2212) 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 Prkdc gene and subsequent glomerular binding of Plg.<\/jats:p>\n               <jats:p>This article has an associated First Person interview with the first author of the paper.<\/jats:p>","DOI":"10.1242\/dmm.049038","type":"journal-article","created":{"date-parts":[[2021,8,23]],"date-time":"2021-08-23T09:18:44Z","timestamp":1629710324000},"source":"Crossref","is-referenced-by-count":5,"title":["Essential role of DNA-PKcs and plasminogen for the development of doxorubicin-induced glomerular injury in mice"],"prefix":"10.1242","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0169-3948","authenticated-orcid":false,"given":"Bernhard N.","family":"Bohnert","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, Division of Endocrinology, Diabetology and Nephrology, University Hospital T\u00fcbingen, 72076 T\u00fcbingen, Germany"},{"name":"Institute of Diabetes Research and Metabolic Diseases (IDM) of the Helmholtz Center Munich at the University T\u00fcbingen, 72076 T\u00fcbingen, Germany"},{"name":"German Center for Diabetes Research (DZD), University T\u00fcbingen, 72076 T\u00fcbingen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Irene","family":"Gonzalez-Menendez","sequence":"additional","affiliation":[{"name":"Institute of Pathology and Neuropathology, Department of Pathology, Eberhard Karls University of T\u00fcbingen and Comprehensive Cancer Center, University Hospital T\u00fcbingen, 72076 T\u00fcbingen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas","family":"D\u00f6rffel","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Endocrinology, Diabetology and Nephrology, University Hospital T\u00fcbingen, 72076 T\u00fcbingen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jonas C.","family":"Schneider","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Endocrinology, Diabetology and Nephrology, University Hospital T\u00fcbingen, 72076 T\u00fcbingen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mengyun","family":"Xiao","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Endocrinology, Diabetology and Nephrology, University Hospital T\u00fcbingen, 72076 T\u00fcbingen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrea","family":"Janessa","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Endocrinology, Diabetology and Nephrology, University Hospital T\u00fcbingen, 72076 T\u00fcbingen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M. Zaher","family":"Kalo","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Endocrinology, Diabetology and Nephrology, University Hospital T\u00fcbingen, 72076 T\u00fcbingen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Birgit","family":"Fehrenbacher","sequence":"additional","affiliation":[{"name":"Department of Dermatology, University Hospital T\u00fcbingen, 72076 T\u00fcbingen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Martin","family":"Schaller","sequence":"additional","affiliation":[{"name":"Department of Dermatology, University Hospital T\u00fcbingen, 72076 T\u00fcbingen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nicolas","family":"Casadei","sequence":"additional","affiliation":[{"name":"Institute of Genetics, University Hospital T\u00fcbingen, 72076 T\u00fcbingen, Germany"},{"name":"NGS Competence Center T\u00fcbingen, University T\u00fcbingen, T\u00fcbingen 72076, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kerstin","family":"Amann","sequence":"additional","affiliation":[{"name":"Institute of Pathology, Department of Nephropathology, Friedrich-Alexander University Erlangen-N\u00fcrnberg (FAU), 91054 Erlangen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christoph","family":"Daniel","sequence":"additional","affiliation":[{"name":"Institute of Pathology, Department of Nephropathology, Friedrich-Alexander University Erlangen-N\u00fcrnberg (FAU), 91054 Erlangen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andreas L.","family":"Birkenfeld","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Endocrinology, Diabetology and Nephrology, University Hospital T\u00fcbingen, 72076 T\u00fcbingen, Germany"},{"name":"Institute of Diabetes Research and Metabolic Diseases (IDM) of the Helmholtz Center Munich at the University T\u00fcbingen, 72076 T\u00fcbingen, Germany"},{"name":"German Center for Diabetes Research (DZD), University T\u00fcbingen, 72076 T\u00fcbingen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Florian","family":"Grahammer","sequence":"additional","affiliation":[{"name":"III. Department of Medicine, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lahoucine","family":"Izem","sequence":"additional","affiliation":[{"name":"Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Edward F.","family":"Plow","sequence":"additional","affiliation":[{"name":"Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7156-5365","authenticated-orcid":false,"given":"Leticia","family":"Quintanilla-Martinez","sequence":"additional","affiliation":[{"name":"Institute of Pathology and Neuropathology, Department of Pathology, Eberhard Karls University of T\u00fcbingen and Comprehensive Cancer Center, University Hospital T\u00fcbingen, 72076 T\u00fcbingen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3777-9316","authenticated-orcid":false,"given":"Ferruh","family":"Artunc","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Endocrinology, Diabetology and Nephrology, University Hospital T\u00fcbingen, 72076 T\u00fcbingen, Germany"},{"name":"Institute of Diabetes Research and Metabolic Diseases (IDM) of the Helmholtz Center Munich at the University T\u00fcbingen, 72076 T\u00fcbingen, Germany"},{"name":"German Center for Diabetes Research (DZD), University T\u00fcbingen, 72076 T\u00fcbingen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"237","published-online":{"date-parts":[[2021,9,15]]},"reference":[{"key":"2021100110373527100_DMM049038C1","doi-asserted-by":"publisher","first-page":"F1624","DOI":"10.1152\/ajprenal.00032.2008","article-title":"Serum- and glucocorticoid-inducible kinase 1 in doxorubicin-induced nephrotic syndrome","volume":"295","author":"Artunc","year":"2008","journal-title":"Am. J. Physiol. Renal Physiol."},{"key":"2021100110373527100_DMM049038C2","doi-asserted-by":"publisher","first-page":"e13249","DOI":"10.1111\/apha.13249","article-title":"Proteasuria-The impact of active urinary proteases on sodium retention in nephrotic syndrome","volume":"225","author":"Artunc","year":"2019","journal-title":"Acta Physiol."},{"key":"2021100110373527100_DMM049038C3","author":"Bissinger","year":"2021"},{"key":"2021100110373527100_DMM049038C4","doi-asserted-by":"publisher","first-page":"57642","DOI":"10.3791\/57642","article-title":"Induction of nephrotic syndrome in mice by retrobulbar injection of doxorubicin and prevention of volume retention by sustained release aprotinin","author":"Bohnert","year":"2018","journal-title":"J. Vis. Exp."},{"key":"2021100110373527100_DMM049038C5","doi-asserted-by":"publisher","first-page":"153","DOI":"10.1159\/000368491","article-title":"Impact of phosphorus restriction and vitamin D-substitution on secondary hyperparathyroidism in a proteinuric mouse model","volume":"40","author":"Bohnert","year":"2015","journal-title":"Kidney Blood Press. Res."},{"key":"2021100110373527100_DMM049038C6","doi-asserted-by":"publisher","first-page":"159","DOI":"10.1016\/j.kint.2017.07.023","article-title":"Aprotinin prevents proteolytic epithelial sodium channel (ENaC) activation and volume retention in nephrotic syndrome","volume":"93","author":"Bohnert","year":"2018","journal-title":"Kidney Int."},{"key":"2021100110373527100_DMM049038C7","doi-asserted-by":"publisher","first-page":"e13286","DOI":"10.1111\/apha.13286","article-title":"Urokinase-type plasminogen activator (uPA) is not essential for epithelial sodium channel (ENaC)-mediated sodium retention in experimental nephrotic syndrome","volume":"227","author":"Bohnert","year":"2019","journal-title":"Acta Physiol."},{"key":"2021100110373527100_DMM049038C8","doi-asserted-by":"publisher","first-page":"564","DOI":"10.1177\/0023677218824382","article-title":"Retrobulbar sinus injection of doxorubicin is more efficient than lateral tail vein injection at inducing experimental nephrotic syndrome in mice: a pilot study","volume":"53","author":"Bohnert","year":"2019","journal-title":"Lab. Anim."},{"key":"2021100110373527100_DMM049038C9","doi-asserted-by":"publisher","first-page":"794","DOI":"10.1101\/gad.9.7.794","article-title":"Plasminogen deficiency causes severe thrombosis but is compatible with development and reproduction","volume":"9","author":"Bugge","year":"1995","journal-title":"Genes Dev."},{"key":"2021100110373527100_DMM049038C10","doi-asserted-by":"publisher","first-page":"3763","DOI":"10.1182\/blood-2007-03-079392","article-title":"Histone H2B as a functionally important plasminogen receptor on macrophages","volume":"110","author":"Das","year":"2007","journal-title":"Blood"},{"key":"2021100110373527100_DMM049038C11","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1016\/j.dnarep.2014.02.020","article-title":"DNA-PK: a dynamic enzyme in a versatile DSB repair pathway","volume":"17","author":"Davis","year":"2014","journal-title":"DNA Repair"},{"key":"2021100110373527100_DMM049038C12","doi-asserted-by":"publisher","first-page":"16191","DOI":"10.1096\/fj.202000413R","article-title":"Plasminogenuria is associated with podocyte injury, edema, and kidney dysfunction in incident glomerular disease","volume":"34","author":"Egerman","year":"2020","journal-title":"FASEB J."},{"key":"2021100110373527100_DMM049038C13","doi-asserted-by":"publisher","first-page":"493","DOI":"10.1667\/RR2431.1","article-title":"Murine Prkdc polymorphisms impact DNA-PKcs function","volume":"175","author":"Fabre","year":"2011","journal-title":"Radiat. Res."},{"key":"2021100110373527100_DMM049038C14","doi-asserted-by":"publisher","first-page":"e13060","DOI":"10.1111\/apha.13060","article-title":"Plasma kallikrein activates the epithelial sodium channel in vitro but is not essential for volume retention in nephrotic mice","volume":"224","author":"Haerteis","year":"2018","journal-title":"Acta Physiol."},{"key":"2021100110373527100_DMM049038C15","doi-asserted-by":"publisher","first-page":"9463","DOI":"10.1021\/bi060756w","article-title":"Identification of histone H2B as a regulated plasminogen receptor","volume":"45","author":"Herren","year":"2006","journal-title":"Biochemistry"},{"key":"2021100110373527100_DMM049038C16","doi-asserted-by":"publisher","first-page":"207","DOI":"10.1097\/MNH.0000000000000578","article-title":"Mechanisms of sodium retention in nephrotic syndrome","volume":"29","author":"Hinrichs","year":"2020","journal-title":"Curr. Opin. Nephrol. Hypertens."},{"key":"2021100110373527100_DMM049038C17","doi-asserted-by":"publisher","first-page":"bay119","DOI":"10.1093\/database\/bay119","article-title":"Ensembl variation resources","volume":"2018","author":"Hunt","year":"2018","journal-title":"Database"},{"key":"2021100110373527100_DMM049038C18","doi-asserted-by":"publisher","first-page":"941","DOI":"10.1111\/jth.15253","article-title":"Plasminogen-induced foam cell formation by macrophages occurs through a histone 2B (H2B)-PAR1 pathway and requires integrity of clathrin-coated pits","volume":"19","author":"Izem","year":"2021","journal-title":"J. Thromb. Haemost."},{"key":"2021100110373527100_DMM049038C19","doi-asserted-by":"publisher","first-page":"114","DOI":"10.1681\/ASN.2007111205","article-title":"Adriamycin alters glomerular endothelium to induce proteinuria","volume":"20","author":"Jeansson","year":"2009","journal-title":"J. Am. Soc. Nephrol."},{"key":"2021100110373527100_DMM049038C20","doi-asserted-by":"publisher","first-page":"963","DOI":"10.1084\/jem.185.5.963","article-title":"Plasminogen and plasminogen activators protect against renal injury in crescentic glomerulonephritis","volume":"185","author":"Kitching","year":"1997","journal-title":"J. Exp. Med."},{"key":"2021100110373527100_DMM049038C21","doi-asserted-by":"publisher","first-page":"D1062","DOI":"10.1093\/nar\/gkx1153","article-title":"ClinVar: improving access to variant interpretations and supporting evidence","volume":"46","author":"Landrum","year":"2018","journal-title":"Nucleic Acids Res."},{"key":"2021100110373527100_DMM049038C22","doi-asserted-by":"publisher","first-page":"1712","DOI":"10.3390\/ijms22041712","article-title":"Plasminogen receptors and fibrinolysis","volume":"22","author":"Miles","year":"2021","journal-title":"Int. J. Mol. Sci."},{"key":"2021100110373527100_DMM049038C23","doi-asserted-by":"publisher","first-page":"686","DOI":"10.1111\/j.1349-7006.2003.tb01503.x","article-title":"Distinct mechanisms of site-specific oxidative DNA damage by doxorubicin in the presence of copper(II) and NADPH-cytochrome P450 reductase","volume":"94","author":"Mizutani","year":"2003","journal-title":"Cancer Sci."},{"key":"2021100110373527100_DMM049038C24","doi-asserted-by":"publisher","first-page":"e0231223","DOI":"10.1371\/journal.pone.0231223","article-title":"Doxorubicin induces large-scale and differential H2A and H2B redistribution in live cells","volume":"15","author":"N\u00e1n\u00e1si","year":"2020","journal-title":"PLoS ONE"},{"key":"2021100110373527100_DMM049038C25","doi-asserted-by":"publisher","first-page":"4055","DOI":"10.1172\/JCI43721","article-title":"Prkdc participates in mitochondrial genome maintenance and prevents Adriamycin-induced nephropathy in mice","volume":"120","author":"Papeta","year":"2010","journal-title":"J. Clin. Invest."},{"key":"2021100110373527100_DMM049038C26","doi-asserted-by":"publisher","first-page":"2005","DOI":"10.1182\/blood.V91.6.2005","article-title":"Plasminogen deficiency differentially affects recruitment of inflammatory cell populations in mice","volume":"91","author":"Ploplis","year":"1998","journal-title":"Blood"},{"key":"2021100110373527100_DMM049038C27","doi-asserted-by":"publisher","first-page":"141806","DOI":"10.1155\/2012\/141806","article-title":"So many plasminogen receptors: why?","volume":"2012","author":"Plow","year":"2012","journal-title":"J. Biomed. Biotechnol."},{"key":"2021100110373527100_DMM049038C28","doi-asserted-by":"publisher","first-page":"F1308","DOI":"10.1152\/ajprenal.00162.2016","article-title":"Podocyte injury: the role of proteinuria, urinary plasminogen, and oxidative stress","volume":"311","author":"Raij","year":"2016","journal-title":"Am. J. Physiol. Renal Physiol."},{"key":"2021100110373527100_DMM049038C29","doi-asserted-by":"publisher","first-page":"299","DOI":"10.1681\/ASN.2008040364","article-title":"Plasmin in nephrotic urine activates the epithelial sodium channel","volume":"20","author":"Svenningsen","year":"2009","journal-title":"J. Am. Soc. Nephrol."},{"key":"2021100110373527100_DMM049038C30","doi-asserted-by":"publisher","first-page":"799","DOI":"10.1016\/S0002-9440(10)64239-3","article-title":"A new method for large scale isolation of kidney glomeruli from mice","volume":"161","author":"Takemoto","year":"2002","journal-title":"Am. J. Pathol."},{"key":"2021100110373527100_DMM049038C31","doi-asserted-by":"publisher","first-page":"1797","DOI":"10.1046\/j.1523-1755.2000.00342.x","article-title":"Progressive adriamycin nephropathy in mice: sequence of histologic and immunohistochemical events","volume":"58","author":"Wang","year":"2000","journal-title":"Kidney Int."},{"key":"2021100110373527100_DMM049038C32","doi-asserted-by":"publisher","first-page":"e13512","DOI":"10.1111\/apha.13512","article-title":"Plasminogen deficiency does not prevent sodium retention in a genetic mouse model of experimental nephrotic syndrome","volume":"231","author":"Xiao","year":"2021","journal-title":"Acta Physiol."},{"key":"2021100110373527100_DMM049038C33","first-page":"1820","article-title":"Elevated breast cancer risk in irradiated BALB\/c mice associates with unique functional polymorphism of the Prkdc (DNA-dependent protein kinase catalytic subunit) gene","volume":"61","author":"Yu","year":"2001","journal-title":"Cancer Res."},{"key":"2021100110373527100_DMM049038C34","doi-asserted-by":"publisher","first-page":"2502","DOI":"10.1073\/pnas.0409786102","article-title":"A mendelian locus on chromosome 16 determines susceptibility to doxorubicin nephropathy in the mouse","volume":"102","author":"Zheng","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2021100110373527100_DMM049038C35","doi-asserted-by":"publisher","first-page":"1796","DOI":"10.1681\/ASN.2005121373","article-title":"An ancestral haplotype defines susceptibility to doxorubicin nephropathy in the laboratory mouse","volume":"17","author":"Zheng","year":"2006","journal-title":"J. Am. Soc. Nephrol."}],"container-title":["Disease Models &amp; Mechanisms"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/journals.biologists.com\/dmm\/article-pdf\/doi\/10.1242\/dmm.049038\/2101872\/dmm049038.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"http:\/\/journals.biologists.com\/dmm\/article-pdf\/doi\/10.1242\/dmm.049038\/2107457\/dmm049038.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/journals.biologists.com\/dmm\/article-pdf\/doi\/10.1242\/dmm.049038\/2107457\/dmm049038.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,10,1]],"date-time":"2021-10-01T10:50:33Z","timestamp":1633085433000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.biologists.com\/dmm\/article\/14\/9\/dmm049038\/272175\/Essential-role-of-DNA-PKcs-and-plasminogen-for-the"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,9,1]]},"references-count":35,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2021,9,1]]}},"URL":"https:\/\/doi.org\/10.1242\/dmm.049038","relation":{},"ISSN":["1754-8403","1754-8411"],"issn-type":[{"value":"1754-8403","type":"print"},{"value":"1754-8411","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,9,1]]},"article-number":"dmm049038"}}