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2011 Fiscal Year Final Research Report

Kidney-specific overexpression of Sirt1 protects against chronic kidney disease.

Research Project

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Project/Area Number 22790800
Research Category

Grant-in-Aid for Young Scientists (B)

Allocation TypeSingle-year Grants
Research Field Kidney internal medicine
Research InstitutionKeio University

Principal Investigator

HASEGAWA Kazuhiro  慶應義塾大学, 医学部, 特任助教 (30424162)

Project Period (FY) 2010 – 2011
Keywords慢性腎臓病 / 近位尿細管 / Sirt1
Research Abstract

NAD-dependent deacetylase, Sirt1 confers protective effects in various tissues. Although it has been reported that whole body Sirt1 induction by calorie restriction or specific Sirt1 activators increases insulin secretion or attenuates insulin resistance, the role of kidney Sirt1 in diabetic nephropathy has not been elucidated. We previously reported that our Tg mice with kidney-specific overexpression of Sirt1 protected against AKI(JBC 2010). However, a correlation between renal Sirt1 and CKD is unclear. Here, we explore the role of renal Sirt1 in diabetic nephropathy(DN). WT or Tg mice were rendered DN by the treatment with streptozotocin(STZ). Eight weeks old male WT or Sirt1 Tg mice were subjected to intraperitoneal injection of saline(control) or streptozotocin with 50mg/kg/day for 5 days(WT+Sal, WT+STZ, Tg+Sal, Tg+STZ). After 2 or 6 months, we measured various blood and urine parameters, and kidney histology. WT+STZ mice were presented with prominent albuminuria with podocytes foot process effacement. Sirt1 expression was decreased in proximal tubules as well as podocotyes. Among various molecules, tight junction protein claudin-1, a parietal epithelial cell marker, was ectopically upregulated in podocytes. Conversely, these findings were attenuated in Tg+STZ. In podocytes with the direct transfection of claudin-1, the expressions of slit diaphragm proteins, podocin and synaptopodin were downregulated and albumin permeability was significantly increased. In non-DN state, Sirt1 downregulated claudin-1 expression. Oppositely, in DN, HG-induced Sirt1 downregulation increased the claudin-1 expression leading to the downregulation of slit diaphragm proteins and to the increase in podocytes' albumin permeability. This novel mechanism contributes to albuminuria in DN.

  • Research Products

    (6 results)

All 2011 2010

All Journal Article (1 results) (of which Peer Reviewed: 1 results) Presentation (5 results)

  • [Journal Article] Kidney-specific overexpression of Sirt1 protects against acute kidney injury by retaining peroxisome function2010

    • Author(s)
      Hasegawa K, Wakino S, Yoshioka K, Tatematsu S, Hara Y, Minakuchi H, Sueyasu K, Washida N, Tokuyama H, Tzukerman M, Skorecki K, Hayashi K, Itoh H
    • Journal Title

      J Biol Chem

      Volume: 285(17) Pages: 13045-56

    • Peer Reviewed
  • [Presentation] Epigenetic CpG Methylation of Tight Junction Protein, Claudin-1 through Sirt1 and Dnmt1 Controls Albuminuria in Diabetic Nephropathy2011

    • Author(s)
      Kazuhiro Hasegawa, Shu Wakino, Koichi Hayashi, Hiroshi Itoh
    • Organizer
      第44回米国腎臓病学会
    • Place of Presentation
      フィラデルフィア、米国
    • Year and Date
      20111108-13
  • [Presentation] Proximal Tubules-Specific Sirt1-Deficient Mice Aggravates Albuminuria in Diabetic Nephropathy by Accelerating De-Differentiation of Podocytes2011

    • Author(s)
      Kazuhiro Hasegawa, Shu Wakino, Koichi Hayashi, Hiroshi Itoh
    • Organizer
      第44回米国腎臓病学会
    • Place of Presentation
      フィラデルフィア、米国
    • Year and Date
      20111108-13
  • [Presentation] 尿細管Sirt1過剰発現マウスは、糖尿病性腎症のclaudin-1異所性高発現を改善し、アルブミン尿を低下させる2011

    • Author(s)
      長谷川一宏、脇野修、林晃一、伊藤裕
    • Organizer
      第54回日本腎臓病学会
    • Place of Presentation
      横浜
    • Year and Date
      20110615-17
  • [Presentation] Kidney-specific overexpression of Sirt1 protects against chronic kidney disease2010

    • Author(s)
      Hasegawa K, Wakino S, Hayashi K, Itoh H
    • Organizer
      米国腎臓病学会
    • Place of Presentation
      デンバー
    • Year and Date
      2010-11-19
  • [Presentation] 尿細管特異的Sirt1マウスのCKD抑制効果の検証2010

    • Author(s)
      長谷川一宏、脇野修、林晃一、伊藤裕
    • Organizer
      第54回日本腎臓学会学術総会
    • Place of Presentation
      神戸
    • Year and Date
      2010-06-16

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Published: 2013-07-31  

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