Differential effects of glyoxalase 1 overexpression on diabetic atherosclerosis and renal dysfunction in streptozotocin-treated, apolipoprotein E-deficient mice

Abstract

The reactive dicarbonyls, glyoxal and methylglyoxal (MG), increase in diabetes and may participate in the development of diabetic complications. Glyoxal and MG are detoxified by the sequential activities of glyoxalase 1 (GLO1) and glyoxalase 2. To determine the contribution of these dicarbonyls to the etiology of complications, we have genetically manipulated GLO1 levels in apolipoprotein E‐null (Apoe−/−) mice. Male Apoe−/− mice, hemizygous for a human GLO1 transgene (GLO1TGApoe−/− mice) or male nontransgenic Apoe−/− litter mates were injected with streptozotocin or vehicle and 6 or 20 weeks later, aortic atherosclerosis was quantified. The GLO1 transgene lessened streptozotocin (STZ)‐induced increases in immunoreactive hydroimidazolone (MG‐H1). Compared to nondiabetic mice, STZ‐treated GLO1TGApoe−/− and Apoe−/− mice had increased serum cholesterol and triglycerides and increased atherosclerosis at both times after diabetes induction. While the increased GLO1 activity in the GLO1TGApoe−/− mice failed to protect against diabetic atherosclerosis, it lessened glomerular mesangial expansion, prevented albuminuria and lowered renal levels of dicarbonyls and protein glycation adducts. Aortic atherosclerosis was also quantified in 22‐week‐old, male normoglycemic Glo1 knockdown mice on an Apoe−/− background (Glo1KDApoe−/− mice), an age at which Glo1KD mice exhibit albuminuria and renal pathology similar to that of diabetic mice. In spite of ~75% decrease in GLO1 activity and increased aortic MG‐H1, the Glo1KDApoe−/− mice did not show increased atherosclerosis compared to age‐matched Apoe−/− mice. Thus, manipulation of GLO1 activity does not affect the development of early aortic atherosclerosis in Apoe−/− mice but can dictate the onset of kidney disease independently of blood glucose levels.

The role of methylglyoxal and the glyoxalase system in diabetes and other age-related diseases

“…Comparable results have been obtained by Geoffrion et al [121], who found no effects on diabetic atherosclerosis of either GLO1 overexpression or GLO1 knockdown. In contrast, exposure to MGO, either from an exogeneous source or generated after inhibition of GLO1, is able to augment atherogenesis in ApoE −/− mice, with a similar magnitude to that observed in diabetic mice [156].…”

“…In line with this, it has been demonstrated that overexpression of GLO1 in streptozotocin-induced diabetic rats improves renal function and protects against albuminuria [99,121,122]. The importance of GLO1 for normal kidney functioning has also been confirmed by a recent study in non-diabetic mice, in which a reduction in GLO1 by siRNA was found to increase MG-H1 residues in proteins of renal glomeruli and tubules, accompanied by the development of albuminuria and mesangial expansion [123].…”

Advanced glycation end products in the pathogenesis of chronic kidney disease

“…85 Therapeutic agents that induce Glo1 expression may be better because: (i) Glo1 metabolises >97% of MG formed in human metabolism; 10 (ii) they correct decreased renal Glo1 activity which is a common characteristic of animal models of DKD; [86][87][88] and (iii) pre-clinical studies showing decreased Glo1 expression potentiates and overexpression of Glo1 prevents the development of diabetic nephropathy. 7,12,89 Small molecule inducers of Glo1 expression or "Glo1 inducers" may be developed as activators of Nrf2, exploiting a regulatory antioxidant response element (ARE) in the GLO1 gene. Glo1 inducers decreased cellular and extracellular concentrations of MG, MG-derived AGE formation and related functional impairment -such as endothelial attachment to collagen-4.…”

Multiple roles of glyoxalase 1-mediated suppression of methylglyoxal glycation in cancer biology—Involvement in tumour suppression, tumour growth, multidrug resistance and target for chemotherapy

“…The association of increased Glo1 expression with tumour growth may suggest GLO1 is an oncogene [31]. However, increased expression of Glo1 or mutation of Glo1 does not drive malignant transformation in vitro or in vivo [32,33]. This suggests that GLO1 is not an oncogene [32,34].…”