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.

Dicarbonyl stress in cell and tissue dysfunction contributing to ageing and disease

“…Decreased Glo1 expression by hypoxia and inflammation, hypoxiainduced increased anaerobic glycolysis and decreased disposal of triosephosphates by the reductive pentosephosphate pathway (enzymes of which are inhibited by uraemic toxins) leading to increased formation of MG are likely causes. Ageing-related decline in renal function and interstitial thickening was prevented in transgenic rats overexpressing Glo1 [35].…”

Glycative stress and glyoxalase in kidney disease and aging

“…Ikeda et al [5] investigated the aging phenotypes in GLO1-Tg rats. The results showed that renal Glo1 activity was significantly decreased with age, and it was associated with an increase in glycative stress (estimated by accumulation of CEL) with age.…”

“…Taken together, kidney aging was associated with both oxidative and glycative stress. In addition, Glo1 delayed the renal senescence phenotypes via the alteration of these stresses [5].…”

“…Taken together, these results demonstrate that Glo1 activity was decreased with age and contributed to kidney aging phenotypic changes. From the point of view that glycative stress is linked to kidney aging, prevention of age-associated Glo1 lowering to regulate glycative and oxidative stress state may be beneficial to delay kidney aging and to maintain young and healthy kidney cells [5].…”

Role of Uremic Toxins in Erythropoiesis-Stimulating Agent Resistance in Chronic Kidney Disease and Dialysis Patients

“…Glycative stress in CKD patients plays an important role in the pathogenesis of a variety of CKD complications. In addition, studies of transgenic rats overexpressing glyoxalse 1 (GLO1), which detoxifies precursors of AGE, demonstrated that glycative stress causes renal senescence 15 and vascular endothelial dysfunction. 16 GLO1-transgenic-aged rats showed amelioration of renal senescence as assessed by expression levels of senescence markers such as p53, p21 (WAF1/CIP1), and p16 (INK4A) and a positive rate of senescence-associated b-galactosidase staining.…”