title: Glyoxalase I retards renal senescence.
abstract: Although kidney functions deteriorate with age, little is known about the general morphological alterations and mechanisms of renal senescence. We hypothesized that carbonyl stress causes senescence and investigated the possible role of glyoxalase I (GLO1), which detoxifies precursors of advanced glycation end products in the aging process of the kidney. We observed amelioration of senescence in GLO1-transgenic aged rats (assessed by expression levels of senescence markers such as p53, p21(WAF1/CIP1), and p16(INK4A)) and a positive rate of senescence-associated β-galactosidase (SABG) staining, associated with reduction of renal advanced glycation end product accumulation (estimated by the amount of carboxyethyl lysine). GLO1-transgenic rats showed amelioration of interstitial thickening (observed as an age-related presentation in human renal biopsy specimens) and were protected against age-dependent decline of renal functions. We used GLO1 overexpression or knockdown in primary renal proximal tubular epithelial cells to investigate the effect of GLO1 on cellular senescence. Senescence markers were significantly up-regulated in renal proximal tubular epithelial cells at late passage and in those treated with etoposide, a chemical inducer of senescence. GLO1 cellular overexpression ameliorated and knockdown enhanced the cellular senescence phenotypes. Furthermore, we confirmed the association of decreased GLO1 enzymatic activity and age-dependent deterioration of renal function in aged humans with GLO1 mutation. These findings indicate that GLO1 ameliorates carbonyl stress to retard renal senescence.
authors: Division of Nephrology and Endocrinology, Graduate School of Medicine, the University of Tokyo, Tokyo, Japan.
authors: Yoichiro
authors: Y
authors: Ikeda
authors: Reiko
authors: R
authors: Inagi
authors: Toshio
authors: T
authors: Miyata
authors: Ryoji
authors: R
authors: Nagai
authors: Makoto
authors: M
authors: Arai
authors: Mitsuhiro
authors: M
authors: Miyashita
authors: Masanari
authors: M
authors: Itokawa
authors: Toshiro
authors: T
authors: Fujita
authors: Masaomi
authors: M
authors: Nangaku
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D016922:Cellular Senescence / Q000187:drug effects / Q000502:physiology*; D005047:Etoposide / Q000494:pharmacology; D016368:Frameshift Mutation / Q000235:genetics; D055785:Gene Knockdown Techniques; D005919:Glomerular Filtration Rate / Q000502:physiology; D017127:Glycation End Products, Advanced / Q000378:metabolism; D006801:Humans; D007672:Kidney Cortex / Q000166:cytology* / Q000201:enzymology; D007674:Kidney Diseases / Q000235:genetics; D007684:Kidney Tubules / Q000166:cytology* / Q000201:enzymology; D007791:Lactoylglutathione Lyase / Q000235:genetics / Q000502:physiology*; D008875:Middle Aged; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D012559:Schizophrenia / Q000503:physiopathology; D013482:Superoxide Dismutase / Q000378:metabolism; D001616:beta-Galactosidase / Q000378:metabolism
chemical_list: D015415:Biomarkers; D017127:Glycation End Products, Advanced; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D005047:Etoposide; D013482:Superoxide Dismutase; D001616:beta-Galactosidase; D007791:Lactoylglutathione Lyase