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dc.contributor.authorHasegawa, Kazuhiro
dc.contributor.authorWakino, Shu
dc.contributor.authorSimic, Petra
dc.contributor.authorSakamaki, Yusuke
dc.contributor.authorMinakuchi, Hitoshi
dc.contributor.authorFujimura, Keiko
dc.contributor.authorHosoya, Kozi
dc.contributor.authorKomatsu, Motoaki
dc.contributor.authorKaneko, Yuka
dc.contributor.authorKanda, Takeshi
dc.contributor.authorKubota, Eiji
dc.contributor.authorTokuyama, Hirobumi
dc.contributor.authorHayashi, Koichi
dc.contributor.authorItoh, Hiroshi
dc.contributor.authorGuarente, Leonard Pershing
dc.date.accessioned2015-04-07T18:29:07Z
dc.date.available2015-04-07T18:29:07Z
dc.date.issued2013-10
dc.date.submitted2013-06
dc.identifier.issn1078-8956
dc.identifier.issn1546-170X
dc.identifier.urihttp://hdl.handle.net/1721.1/96409
dc.description.abstractSirtuin 1 (Sirt1), a NAD[superscript +]-regulated deacetylase with numerous known positive effects on cellular and whole-body metabolism, is expressed in the renal cortex and medulla. It is known to have protective effects against age-related disease, including diabetes. Here we investigated the protective role of Sirt1 in diabetic renal damage. We found that Sirt1 in proximal tubules (PTs) was downregulated before albuminuria occurred in streptozotocin-induced or obese (db/db) diabetic mice. PT-specific SIRT1 transgenic and Sirt1 knockout mice showed prevention and aggravation of the glomerular changes that occur in diabetes, respectively, and nondiabetic knockout mice exhibited albuminuria, suggesting that Sirt1 in PTs affects glomerular function. Downregulation of Sirt1 and upregulation of the tight junction protein Claudin-1 by SIRT1-mediated epigenetic regulation in podocytes contributed to albuminuria. We did not observe these phenomena in 5/6 nephrectomized mice. We also demonstrated retrograde interplay from PTs to glomeruli using nicotinamide mononucleotide (NMN) from conditioned medium, measurement of the autofluorescence of photoactivatable NMN and injection of fluorescence-labeled NMN. In human subjects with diabetes, the levels of SIRT1 and Claudin-1 were correlated with proteinuria levels. These results suggest that Sirt1 in PTs protects against albuminuria in diabetes by maintaining NMN concentrations around glomeruli, thus influencing podocyte function.en_US
dc.description.sponsorshipJapan. Ministry of Education, Culture, Sports, Science and Technology (Grant 22790800)en_US
dc.language.isoen_US
dc.publisherNature Publishing Groupen_US
dc.relation.isversionofhttp://dx.doi.org/10.1038/nm.3363en_US
dc.rightsCreative Commons Attribution-Noncommercial-Share Alikeen_US
dc.rights.urihttp://creativecommons.org/licenses/by-nc-sa/4.0/en_US
dc.sourcePMCen_US
dc.titleRenal tubular Sirt1 attenuates diabetic albuminuria by epigenetically suppressing Claudin-1 overexpression in podocytesen_US
dc.typeArticleen_US
dc.identifier.citationHasegawa, Kazuhiro, Shu Wakino, Petra Simic, Yusuke Sakamaki, Hitoshi Minakuchi, Keiko Fujimura, Kozi Hosoya, et al. “Renal Tubular Sirt1 Attenuates Diabetic Albuminuria by Epigenetically Suppressing Claudin-1 Overexpression in Podocytes.” Nature Medicine 19, no. 11 (October 20, 2013): 1496–1504.en_US
dc.contributor.departmentMassachusetts Institute of Technology. Department of Biologyen_US
dc.contributor.mitauthorSimic, Petraen_US
dc.contributor.mitauthorGuarente, Leonard Pershingen_US
dc.relation.journalNature Medicineen_US
dc.eprint.versionAuthor's final manuscripten_US
dc.type.urihttp://purl.org/eprint/type/JournalArticleen_US
eprint.statushttp://purl.org/eprint/status/PeerRevieweden_US
dspace.orderedauthorsHasegawa, Kazuhiro; Wakino, Shu; Simic, Petra; Sakamaki, Yusuke; Minakuchi, Hitoshi; Fujimura, Keiko; Hosoya, Kozi; Komatsu, Motoaki; Kaneko, Yuka; Kanda, Takeshi; Kubota, Eiji; Tokuyama, Hirobumi; Hayashi, Koichi; Guarente, Leonard; Itoh, Hiroshien_US
dc.identifier.orcidhttps://orcid.org/0000-0003-4064-2510
mit.licenseOPEN_ACCESS_POLICYen_US
mit.metadata.statusComplete


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