Glyoxalase i retards renal senescence

Yoichiro Ikeda, Reiko Inagi, Toshio Miyata, Ryoji Nagai, Makoto Arai, Mitsuhiro Miyashita, Masanari Itokawa, Toshiro Fujita, Masaomi Nangaku

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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.

Original languageEnglish
Pages (from-to)2810-2821
Number of pages12
JournalAmerican Journal of Pathology
Volume179
Issue number6
DOIs
Publication statusPublished - 2011 Dec 1

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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    Ikeda, Y., Inagi, R., Miyata, T., Nagai, R., Arai, M., Miyashita, M., Itokawa, M., Fujita, T., & Nangaku, M. (2011). Glyoxalase i retards renal senescence. American Journal of Pathology, 179(6), 2810-2821. https://doi.org/10.1016/j.ajpath.2011.08.023