{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T20:10:45Z","timestamp":1790539845424,"version":"4.1.0"},"reference-count":41,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2019,6,12]],"date-time":"2019-06-12T00:00:00Z","timestamp":1560297600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100002924","name":"FEDER","doi-asserted-by":"publisher","award":["PI16\/01900"],"award-info":[{"award-number":["PI16\/01900"]}],"id":[{"id":"10.13039\/501100002924","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002924","name":"FEDER","doi-asserted-by":"publisher","award":["PI16\/02057"],"award-info":[{"award-number":["PI16\/02057"]}],"id":[{"id":"10.13039\/501100002924","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002924","name":"FEDER","doi-asserted-by":"publisher","award":["ISCIII\u2010RETIC REDinREN RD016\/0009"],"award-info":[{"award-number":["ISCIII\u2010RETIC REDinREN RD016\/0009"]}],"id":[{"id":"10.13039\/501100002924","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002924","name":"FEDER","doi-asserted-by":"publisher","award":["CP14\/00133"],"award-info":[{"award-number":["CP14\/00133"]}],"id":[{"id":"10.13039\/501100002924","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002924","name":"FEDER","doi-asserted-by":"publisher","award":["PI15\/00298"],"award-info":[{"award-number":["PI15\/00298"]}],"id":[{"id":"10.13039\/501100002924","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100008433","name":"Consejer\u00eda de Educaci\u00f3n, Juventud y Deporte, Comunidad de Madrid","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100008433","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004587","name":"ISCIII","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002924","name":"FEDER","doi-asserted-by":"publisher","award":["SAF2015\u201071521\u2010REDC"],"award-info":[{"award-number":["SAF2015\u201071521\u2010REDC"]}],"id":[{"id":"10.13039\/501100002924","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002924","name":"FEDER","doi-asserted-by":"publisher","award":["SAF2015\u201063904\u2010R"],"award-info":[{"award-number":["SAF2015\u201063904\u2010R"]}],"id":[{"id":"10.13039\/501100002924","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["pathsocjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Pathology"],"published-print":{"date-parts":[[2019,9]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>PGC\u20101\u03b1 (peroxisome proliferator\u2010activated receptor gamma coactivator\u20101\u03b1, PPARGC1A) regulates the expression of genes involved in energy homeostasis and mitochondrial biogenesis. Here we identify inactivation of the transcriptional regulator PGC\u20101\u03b1 as a landmark for experimental nephrotoxic acute kidney injury (AKI) and describe the <jats:italic>in vivo<\/jats:italic> consequences of PGC\u20101\u03b1 deficiency over inflammation and cell death in kidney injury. Kidney transcriptomic analyses of WT mice with folic acid\u2010induced AKI revealed 1398 up\u2010 and 1627 downregulated genes. Upstream transcriptional regulator analyses pointed to PGC\u20101\u03b1 as the transcription factor potentially driving the observed expression changes with the highest reduction in activity. Reduced PGC\u20101\u03b1 expression was shared by human kidney injury. <jats:italic>Ppargc1a<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> mice had spontaneous subclinical kidney injury characterized by tubulointerstitial inflammation and increased <jats:italic>Ngal<\/jats:italic> expression. Upon AKI, <jats:italic>Ppargc1a<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> mice had lower survival and more severe loss of renal function, tubular injury, and reduction in expression of mitochondrial PGC\u20101\u03b1\u2010dependent genes in the kidney, and an earlier decrease in mitochondrial mass than WT mice. Additionally, surviving <jats:italic>Ppargc1a<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> mice showed higher rates of tubular cell death, compensatory proliferation, expression of proinflammatory cytokines, NF\u2010\u03baB activation, and interstitial inflammatory cell infiltration. Specifically, <jats:italic>Ppargc1a<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> mice displayed increased M1 and decreased M2 responses and expression of the anti\u2010inflammatory cytokine IL\u201010. In cultured renal tubular cells, PGC\u20101\u03b1 targeting promoted spontaneous cell death and proinflammatory responses. In conclusion, PGC\u20101\u03b1 inactivation is a key driver of the gene expression response in nephrotoxic AKI and PGC\u20101\u03b1 deficiency promotes a spontaneous inflammatory kidney response that is magnified during AKI. \u00a9 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley &amp; Sons, Ltd.<\/jats:p>","DOI":"10.1002\/path.5282","type":"journal-article","created":{"date-parts":[[2019,4,15]],"date-time":"2019-04-15T00:27:41Z","timestamp":1555288061000},"page":"65-78","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":103,"title":["PGC\u20101\u03b1 deficiency causes spontaneous kidney inflammation and increases the severity of nephrotoxic AKI"],"prefix":"10.1002","volume":"249","author":[{"given":"Miguel","family":"Fontecha\u2010Barriuso","sequence":"first","affiliation":[{"name":"Deparment of Nephrology, Research Institute\u2010Fundacion Jimenez Diaz Autonoma University  Madrid Spain"},{"name":"REDINREN  Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diego","family":"Mart\u00edn\u2010S\u00e1nchez","sequence":"additional","affiliation":[{"name":"Deparment of Nephrology, Research Institute\u2010Fundacion Jimenez Diaz Autonoma University  Madrid Spain"},{"name":"REDINREN  Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julio M","family":"Martinez\u2010Moreno","sequence":"additional","affiliation":[{"name":"Deparment of Nephrology, Research Institute\u2010Fundacion Jimenez Diaz Autonoma University  Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susana","family":"Carrasco","sequence":"additional","affiliation":[{"name":"Deparment of Nephrology, Research Institute\u2010Fundacion Jimenez Diaz Autonoma University  Madrid Spain"},{"name":"REDINREN  Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olga","family":"Ruiz\u2010Andr\u00e9s","sequence":"additional","affiliation":[{"name":"Deparment of Nephrology, Research Institute\u2010Fundacion Jimenez Diaz Autonoma University  Madrid Spain"},{"name":"REDINREN  Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Monsalve","sequence":"additional","affiliation":[{"name":"Department of Metabolism and Cell Signaling, Instituto de Investigaciones Biom\u00e9dicas \u2018Alberto Sols\u2019 (CSIC\u2010UAM)  Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"Sanchez\u2010Ramos","sequence":"additional","affiliation":[{"name":"Department of Metabolism and Cell Signaling, Instituto de Investigaciones Biom\u00e9dicas \u2018Alberto Sols\u2019 (CSIC\u2010UAM)  Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manuel J","family":"G\u00f3mez","sequence":"additional","affiliation":[{"name":"Bioinformatics Unit, Centro Nacional de Investigaciones Cardiovasculares (CNIC)  Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"Ruiz\u2010Ortega","sequence":"additional","affiliation":[{"name":"Deparment of Nephrology, Research Institute\u2010Fundacion Jimenez Diaz Autonoma University  Madrid Spain"},{"name":"REDINREN  Madrid Spain"},{"name":"School of Medicine UAM  Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7110-6409","authenticated-orcid":false,"given":"Maria D","family":"S\u00e1nchez\u2010Ni\u00f1o","sequence":"additional","affiliation":[{"name":"Deparment of Nephrology, Research Institute\u2010Fundacion Jimenez Diaz Autonoma University  Madrid Spain"},{"name":"REDINREN  Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pablo","family":"Cannata\u2010Ortiz","sequence":"additional","affiliation":[{"name":"Department of Pathology, Research Institute\u00a0\u2013\u00a0Fundaci\u00f3n Jim\u00e9nez D\u00edaz, School of Medicine UAM  Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ramiro","family":"Cabello","sequence":"additional","affiliation":[{"name":"Deparment of Nephrology, Research Institute\u2010Fundacion Jimenez Diaz Autonoma University  Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carmen","family":"Gonzalez\u2010Enguita","sequence":"additional","affiliation":[{"name":"Deparment of Nephrology, Research Institute\u2010Fundacion Jimenez Diaz Autonoma University  Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alberto","family":"Ortiz","sequence":"additional","affiliation":[{"name":"Deparment of Nephrology, Research Institute\u2010Fundacion Jimenez Diaz Autonoma University  Madrid Spain"},{"name":"REDINREN  Madrid Spain"},{"name":"School of Medicine UAM  Madrid Spain"},{"name":"IRSIN  Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0255-5689","authenticated-orcid":false,"given":"Ana B","family":"Sanz","sequence":"additional","affiliation":[{"name":"Deparment of Nephrology, Research Institute\u2010Fundacion Jimenez Diaz Autonoma University  Madrid Spain"},{"name":"REDINREN  Madrid Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2019,6,12]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(11)61454-2"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2014121218"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/nri3743"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2015121376"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1017\/erm.2014.14"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbabio.2013.12.008"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajprenal.00263.2017"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.toxlet.2013.11.014"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI58662"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/ki.2015.332"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature17184"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2016050508"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3762"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2010101073"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1038\/ki.2011.475"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1089\/ars.2016.6698"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9440(10)64425-2"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.107.4.1359"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1089\/ars.2012.4713"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2007050577"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00204-016-1830-8"},{"key":"e_1_2_7_23_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.semnephrol.2016.03.006"},{"key":"e_1_2_7_24_1","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2010020218"},{"key":"e_1_2_7_25_1","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2010030269"},{"key":"e_1_2_7_26_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.13-242123"},{"key":"e_1_2_7_27_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI200215606"},{"key":"e_1_2_7_28_1","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.104.078659"},{"key":"e_1_2_7_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/S2213-8587(15)00261-2"},{"key":"e_1_2_7_30_1","doi-asserted-by":"publisher","DOI":"10.1093\/ndt\/gfx170.MP393"},{"key":"e_1_2_7_31_1","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2015040405"},{"key":"e_1_2_7_32_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nefro.2017.04.004"},{"key":"e_1_2_7_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2013.11.022"},{"key":"e_1_2_7_34_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.taap.2013.09.026"},{"key":"e_1_2_7_35_1","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.92930"},{"key":"e_1_2_7_36_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-03753-4"},{"key":"e_1_2_7_37_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.ki.5002242"},{"key":"e_1_2_7_38_1","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2013020126"},{"key":"e_1_2_7_39_1","doi-asserted-by":"publisher","DOI":"10.1002\/path.5166"},{"key":"e_1_2_7_40_1","doi-asserted-by":"publisher","DOI":"10.1089\/ars.2016.6836"},{"key":"e_1_2_7_41_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2004.09.013"},{"key":"e_1_2_7_42_2","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awt291"}],"container-title":["The Journal of Pathology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fpath.5282","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/path.5282","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/path.5282","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/pathsocjournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/path.5282","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,21]],"date-time":"2025-10-21T10:36:33Z","timestamp":1761042993000},"score":1,"resource":{"primary":{"URL":"https:\/\/pathsocjournals.onlinelibrary.wiley.com\/doi\/10.1002\/path.5282"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,6,12]]},"references-count":41,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2019,9]]}},"alternative-id":["10.1002\/path.5282"],"URL":"https:\/\/doi.org\/10.1002\/path.5282","archive":["Portico"],"relation":{},"ISSN":["0022-3417","1096-9896"],"issn-type":[{"value":"0022-3417","type":"print"},{"value":"1096-9896","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,6,12]]},"assertion":[{"value":"2018-11-08","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2019-04-10","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2019-06-12","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}