While renal functions deteriorate with age, little is known about manifestations and mechanisms ofrenal senescence. Advanced glycation end-products (AGEs) are well known to play a pivotal role insenescence. I hypothesized that primary reduction of AGEs lead to less phenotype of senescence, andinvestigated a role of glyoxalase I (GLO1), which detoxifies chiefly precursor of AGE, dicarbonylcompounds, in the aging process of the kidney. First, I established the system to assess renalsenescence, which included halt of the cellular proliferation (in vitro), interstitial thickening (in vivo),elevated transcript and protein expression levels of p53, p21 WAF1/CIP1 and p16INK4A, and elevatedpositive rate of senescence-associated β-galactosidase (SABG) staining. Next, the renal phenotype ofhistological senescence was assessed by reviewing the human renal biopsy specimen from the patientsof whom renal function was less impaired. Interstitial thickening was demonstrated to be the renalhistological manifestation of senescence. Finally, primary regulation of AGEs by overexpression orknockdown of GLO1 was demonstrated to affect cellular or histological status of renal senescence. Inconclusion, I clarified the renal senescence by senescent marker expression and cellular andpathological phenotypes in vivo and in vitro, and demonstrated amelioration of renal senescence byGLO1 overexpression through reduction of AGE accumulation.
発行年
2010-03-24
日本十進分類法
490
学位名
博士(医学)
学位
doctoral
学位分野
Medical Science (医学)
学位授与機関
University of Tokyo (東京大学)
研究科・専攻
Department of Internal Medicine, Graduate School of Medicine (医学系研究科内科学専攻)
学位授与年月日
2010-03-24
学位授与番号
甲第25958号
学位記番号
博医第3447号
アイテムへのリンクの際はタイトル右肩にある「Permalink」をご利用ください！
Please use "Permalink" at the top right of the title when linking to items!
The establishment of assay system of renal senescence and its regulation
h21_Ikeda.pdf
(1.73MB)
