Abstract
Background/Aims: In rodents, carnosine treatment improves diabetic nephropathy, whereas little is known about the role and function of anserine, the methylated form of carnosine. Methods: Antioxidant activity was measured by oxygen radical absorbance capacity and oxygen stress response in human renal tubular cells (HK-2) by RT-PCR and Western-Immunoblotting. In wildtype (WT) and diabetic mice (db/db), the effect of short-term anserine treatment on blood glucose, proteinuria and vascular permeability was measured. Results: Anserine has a higher antioxidant capacity compared to carnosine (p < 0.001). In tubular cells (HK-2) stressed with 25 mM glucose or 20–100 µM hydrogen peroxide, anserine but not carnosine, increased intracellular heat shock protein (Hsp70) mRNA and protein levels. In HK-2 cells stressed with glucose, co-incubation with anserine also increased hemeoxygenase (HO-1) protein and reduced total protein carbonylation, but had no effect on cellular sirtuin-1 and thioredoxin protein concentrations. Three intravenous anserine injections every 48 h in 12-week-old db/db mice, improved blood glucose by one fifth, vascular permeability by one third, and halved proteinuria (all p < 0.05). Conclusion: Anserine is a potent antioxidant and activates the intracellular Hsp70/HO-1 defense system under oxidative and glycative stress. Short-term anserine treatment in diabetic mice improves glucose homeostasis and nephropathy.
Highlights
L-Carnosine (ß-alanyl-L-histidine) and L-anserine (ß-alanyl-Np-methyl-L-histidine) belong to the group of histidine-containing dipeptides (HDPs)
In patients with type 2 diabetes mellitus (DM), especially in females, we [5,6,7] and others [8,9,10] demonstrated an association of the susceptibility to develop diabetic nephropathy (DN), with a variant in the carnosinase 1 gene (CNDP1), associated with lower carnosinase 1 (CN1) activity [11]
Increased protein carbonylation induced by glucose-stress could be dose-dependently reduced by co-incubation with 0.1 and 1 mM anserine (Figure 2)
Summary
L-Carnosine (ß-alanyl-L-histidine) and L-anserine (ß-alanyl-Np-methyl-L-histidine) belong to the group of histidine-containing dipeptides (HDPs). Carnosine is the most prominent dipeptide, with highest concentrations in the muscle, together with either anserine or ophidine at different ratios [1]. The L-histidine residue, with its imidazole ring, exerts most of the buffering activity, i.e., metal chelation and antioxidant properties of carnosine. Whereas carnosine has extensively been studied, little is known about the function of the methylated imidazole ring of anserine. Recent studies reported both dipeptides to prevent methylglyoxal (MG)-induced advanced glycation end product (AGE) and N epsilon-(Carboxyethyl)lysine (CEL) formation. There was a higher quenching activity of carnosine compared to anserine [30], and a lower anti-crosslinking property of anserine, as compared to carnosine [31]. We investigated in vitro protective actions of anserine on different cellular stress tolerance markers, and the impact of exogenous anserine supplementation in diabetic mice
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