Understanding the biological role of the carnosine-carnosinase system in diabetes & beyond

High levels of serum carnosinase, the enzyme that degrades circulating protective dipeptides (carnosine and anserine), have been associated with the risk of developing diabetic nephropathy.We characterized the presence and the potential meaning of urinary carnosinase in patients with type 2 diabetes (T2D) and in kidney transplant recipients (KTR). In the latter group, we additionally assessed urinary carnosine and anserine (1-methylhistidine) levels. In further in vitro and in vivo studies, we determined whether carnosine alleviates oxidative-carbonyl stress (methylglyoxal)-induced effects, and in diabetic mice we investigated the effect of carnosinase overexpression and carnosine feeding on diabetes-induced changes in glomerular hemodynamics reflected by afferent arteriole vasodilation. In patients with T2D and chronic kidney disease, urinary carnosinase was associated with renal function decline and albuminuria. In KTR, urinary carnosine was reduced , and high urinary carnosinase levels were associated with a higher risk of graft failure, whereas increased levels of urinary 1-methylhistidine were associated with favorable prospective outcomes in this population. In vitro studies showed that carnosine treatment influences redox milieu, but did not affect methylglyoxal-induced cellular changes .In diabetic mice, carnosine supplementation resulted in partial normalization of existing afferent arteriole vasodilation. In diabetic mice overexpressing carnosinase, we found a positive association between serum carnosinase levels and the degree of enlargement of the afferent arteriole. Altogether, the studies in this thesis expand on the existing evidence supporting the evaluation of the carnosine-carnosinase system as a target for the treatment of DN and in other conditions where inflammation prevails