title: Sirtuin1 Maintains Actin Cytoskeleton by Deacetylation of Cortactin in Injured Podocytes.
abstract: Recent studies have highlighted the renoprotective effect of sirtuin1 (SIRT1), a deacetylase that contributes to cellular regulation. However, the pathophysiologic role of SIRT1 in podocytes remains unclear. Here, we investigated the function of SIRT1 in podocytes. We first established podocyte-specific Sirt1 knockout (SIRT1(pod-/-)) mice. We then induced glomerular disease by nephrotoxic serum injection. The increase in urinary albumin excretion and BUN and the severity of glomerular injury were all significantly greater in SIRT1(pod-/-) mice than in wild-type mice. Western blot analysis and immunofluorescence showed a significant decrease in podocyte-specific proteins in SIRT1(pod-/-) mice, and electron microscopy showed marked exacerbation of podocyte injury, including actin cytoskeleton derangement in SIRT1(pod-/-) mice compared with wild-type mice. Protamine sulfate-induced podocyte injury was also exacerbated by podocyte-specific SIRT1 deficiency. In vitro, actin cytoskeleton derangement in H2O2-treated podocytes became prominent when the cells were pretreated with SIRT1 inhibitors. Conversely, this H2O2-induced derangement was ameliorated by SIRT1 activation. Furthermore, SIRT1 activation deacetylated the actin-binding and -polymerizing protein cortactin in the nucleus and facilitated deacetylated cortactin localization in the cytoplasm. Cortactin knockdown or inhibition of the nuclear export of cortactin induced actin cytoskeleton derangement and dissociation of cortactin from F-actin, suggesting the necessity of cytoplasmic cortactin for maintenance of the actin cytoskeleton. Taken together, these findings indicate that SIRT1 protects podocytes and prevents glomerular injury by deacetylating cortactin and thereby, maintaining actin cytoskeleton integrity.
authors.affiliation: Divisions of Nephrology and Endocrinology and.
authors.forename: Shuta
authors.initials: S
authors.lastname: Motonishi
authors.affiliation: Divisions of Nephrology and Endocrinology and mnangaku-tky@umin.ac.jp inagi-npr@umin.ac.jp.
authors.forename: Masaomi
authors.initials: M
authors.lastname: Nangaku
authors.affiliation: Divisions of Nephrology and Endocrinology and.
authors.forename: Takehiko
authors.initials: T
authors.lastname: Wada
authors.affiliation: Divisions of Nephrology and Endocrinology and.
authors.forename: Yu
authors.initials: Y
authors.lastname: Ishimoto
authors.affiliation: Divisions of Nephrology and Endocrinology and.
authors.forename: Takamoto
authors.initials: T
authors.lastname: Ohse
authors.affiliation: Department of Internal Medicine, Tokai University School of Medicine, Kanagawa, Japan;
authors.forename: Taiji
authors.initials: T
authors.lastname: Matsusaka
authors.affiliation: Department of Diabetes and Metabolic Diseases, The University of Tokyo Graduate School of Medicine, Tokyo, Japan;
authors.forename: Naoto
authors.initials: N
authors.lastname: Kubota
authors.affiliation: Department of Analytic Human Pathology, Nippon Medical School, Tokyo, Japan; and.
authors.forename: Akira
authors.initials: A
authors.lastname: Shimizu
authors.affiliation: Department of Diabetes and Metabolic Diseases, The University of Tokyo Graduate School of Medicine, Tokyo, Japan;
authors.forename: Takashi
authors.initials: T
authors.lastname: Kadowaki
authors.affiliation: The First Department of Internal Medicine, Faculty of Medicine, University of Toyama, Toyama, Japan.
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Tobe
authors.affiliation: Divisions of Nephrology and Endocrinology and CKD Pathophysiology and mnangaku-tky@umin.ac.jp inagi-npr@umin.ac.jp.
authors.forename: Reiko
authors.initials: R
authors.lastname: Inagi
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism*; D000818:Animals; D002465:Cell Movement; D002467:Cell Nucleus / Q000378:metabolism; D051356:Cortactin / Q000378:metabolism*; D005921:Glomerulonephritis / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D050199:Podocytes / Q000502:physiology* / Q000648:ultrastructure; D056564:Sirtuin 1 / Q000502:physiology*
chemical_list: D051356:Cortactin; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1
keywords: SIRT1; cortactin; cytoskeleton; podocyte