title: The decreases of nephrin and nuclear WT1 in podocytes may cause albuminuria during the experimental sepsis in mice.
abstract: Sepsis is induced by infectious challenges, and septic organ failure often occurs under local and systemic inflammation. Albuminuria is also evident during sepsis, but little is known about the molecular basis of septic albuminuria. Using lipopolysaccharide (LPS)-treated mice as a sepsis model, we found that the loss of nephrin, a key component for maintaining podocyte slit diaphragm, became evident in accordance with the onset of albuminuria, especially 36 h post-LPS challenge (i.e., albumiuric stage). Likewise, nephrin mRNA levels were decreased to 13% of saline-treated mice. Such a transcriptional suppression of nephrin was associated with the loss of nucleus-localized Wilms tumor-1 (WT1), a transcriptional factor for up-regulating nephrin gene. Thereafter, urinary albumin levels were decreased in mice between 72 and 96 h post-LPS challenge (i.e., recovery-stage). Notably, nuclear localization of WT1 seemed to be normalized, and nephrin mRNA and protein levels returned near the basal level 72 h post-LPS challenge. During LPS-mediated sepsis, there was a transient increase in blood interleukin-1β, a suppressor of nephrin production in podocytes. Therefore, down-regulation of nephrin by the loss in nuclear WT1, along with hyper-cytokinemia, may underlie the mechanisms by which albuminuria is induced by infectious stresses.
authors.affiliation: Division of Molecular Regenerative Medicine, Department of Biochemistry and Molecular Biology, Graduate School of Medicine, Osaka University, Tamadaoka 2-2-B7, Suita, Osaka, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kato
authors.forename: Shinya
authors.initials: S
authors.lastname: Mizuno
authors.forename: Miyuki
authors.initials: M
authors.lastname: Kamimoto
mesh_terms: D000419:Albuminuria / Q000209:etiology*; D000818:Animals; D004195:Disease Models, Animal; D015536:Down-Regulation; D005260:Female; D053583:Interleukin-1beta / Q000097:blood; D008070:Lipopolysaccharides / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D050199:Podocytes / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D018805:Sepsis / Q000150:complications*; D014157:Transcription Factors / Q000378:metabolism; D025721:WT1 Proteins / Q000378:metabolism*
chemical_list: D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D012333:RNA, Messenger; D014157:Transcription Factors; D025721:WT1 Proteins; C113267:nephrin