Dietary glycotoxins: inhibition of reactive products by aminoguanidine facilitates renal clearance and reduces tissue sequestration.

Abstract

Evidence indicates that the metabolic turnover of food-derived reactive orally absorbed advanced glycation end products (AGEs) or glycotoxins (GTs) is delayed, possibly contributing to the tissue damage induced by endogenous AGEs, especially in patients with diabetes and kidney disease. The aim of this study was to explore whether pharmacologic inhibition of dietary AGE bioreactivity by aminoguanidine (AG) can improve turnover and renal excretion of these substances. Normal Sprague-Dawley rats were fed single-labeled [14C]AGE-ovalbumin, double-labeled [14C-125I]AGE-ovalbumin, or control 125I-labeled ovalbumin diet plus free [14C]glucose, with or without AG (0.2% in water). [14C]AGE- and 125I-labeled peptide-associated radioactivity (RA) were compared with AGE immunoreactivity (by enzyme-linked immunosorbent assay) in tissues, serum, and 72-h urine samples. The effect of AG on dietary AGE bioreactivity was assessed by monitoring the inhibition of covalent complex formation between fibronectin (FN) peptide fragments and serum components, after a meal of labeled dietary AGE with or without AG. The radiolabeled AGE diet produced serum absorption and urinary excretion peaks kinetically distinct from those of free [14C]glucose or [125I]ovalbumin. Some 26% of the orally absorbed AGE-ovalbumin was excreted in the urine, whereas after AG treatment, urinary excre-tion of dietary AGEs increased markedly (to>50% of absorbed). More than 60% of tissue-bound RA was found covalently deposited in kidneys and liver, whereas after treatment with AG, tissue AGE deposits were reduced to <15% of the amount found in untreated AGE-fed controls. Sera enriched for dietary GTs formed covalently linked complexes with FN, a process completely inhibitable by AG cotreatment. Amelioration of dietary GT bioreactivity by AG improves renal elimination and prevents tissue deposition of food GTs. This may afford a novel and potentially protective use of AG against excessive tissue AGE toxicity in diabetic patients with renal disease.

Inflammatory mediators are induced by dietary glycotoxins, a major risk factor for diabetic angiopathy

“…However, an interesting correlation between postprandial hyperglycemia and serum levels of MG and 3-deoxyglucosone (46) or a transient increase in the production of reactive oxygen species after a meal in diabetic subjects have been reported (47). In this study, postprandial AGE levels correspond to the amount of AGEs ingested (26,27). Furthermore, the steady-state AGE levels follow a pattern that is consistent with the amount ingested and moves synchronously with the inf lammatory mediators.…”

“…Immunoreagents to MG derivatives and CML-like products, however, have presented invaluable means for animal and clinical correlations (10,11,24,25). It thus has been confirmed that two-thirds of orally absorbed dietary AGEs (Ϸ10% of the amount ingested) are retained in tissues in bioreactive forms (26,27). Evidence supporting pathogenicity of food AGEs in animal models has also emerged; in marked contrast to the severe vascular occlusive lesions forming in diabetic apolipoprotein E-deficient mice or the diabetic glomerulopathy in nonobese diabetic and db͞db mice fed standard chow, marked protection against both pathologies was observed in animals fed a low-AGE (L-AGE) diet (28,29) despite hyperlipidemia and hyperglycemia.…”

Renal accumulation and clearance of advanced glycation end-products in type 2 diabetic nephropathy: effect of angiotensin-converting enzyme and vasopeptidase inhibition

“…In patients with diabetic nephropathy, urinary excretion of CML is reduced, and insufficient clearance may result in increased serum AGE concentrations as well as tissue accumulation of AGEs [26][27][28][29]. This is further supported by the fact that the AGE inhibitor aminoguanidine improved renal function in diabetic nephropathy, reduced tissue AGE deposits [30][31][32] and increased urinary excretion of dietary AGEs [33]. In the present study, we observed increased CML clearance in the AVE7688 group, indicating that enhanced excretion may contribute to the reduction of plasma and tissue levels of CML.…”

“…In addition to excretion, exogenous supply and endogenous formation of AGEs are important determinants of serum AGE levels. Chronic exposure of rats to high levels of exogenous AGE can induce morphological kidney damage [33,37]. In the present study, the composition of the chow was controlled and average daily food intake was similar across the groups, which excludes the confounding effects of exogenous AGEs.…”

High dietary advanced glycation end products are associated with poorer spatial learning and accelerated Aβ deposition in an Alzheimer mouse model

“…There are two well‐characterized compounds, N ‐carboxy methyl‐lysine (CML) and methyl‐glyoxal (MG), derivatives of glucose–protein or glucose–lipid interactions, which serve as markers for AGEs (Dyer et al ., 1992; Vlassara & Palace, 2002). A positive correlation is shown between the amount of AGEs consumed and that found in the circulation (Koschinsky et al ., 1997; He et al ., 1999). Consistent with our findings of high serum MG association with faster cognitive decline, we have shown that in the elderly, consumption of high dietary AGEs is associated with a faster rate of cognitive decline (Cai et al ., 2014).…”