The role of carnosinase-1 and its mechanism in the progression of chronic kidney disease

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Carnosine is a natural dipeptide present in mammalian tissues and available as an over-the-counter food additive. In humans, beneficial effects of carnosine have been shown in clinical trials in exercise physiology, psychology, psychiatry, and recently in pre-diabetic overweight volunteers. Although the potential mechanisms of carnosine's action, i.e. lowering chronic low-grade inflammation, oxidative stress, advanced glycation, and lipidoxidation end products (AGEs and ALEs, respectively), on diabetic complications have been suggested, the role of carnosinase-1 (CN-1) in the progression of chronic kidney disease (CKD) is incompletely understood. In line with data from cross-sectional studies in patients with type 2 diabetes that muscle carnosine levels are decreased, the current cooperative project hypothesizes that an increased renal CN-1 expression will deplete renal HCD stores making renal tissue more prone to hyperglycemia mediated damage. The beneficial effect of carnosine supplementation in diabetic models is attributed to its tissue protective properties and in part to its hyperglycemia lowering propensity, ultimately leading to diminished hyperfiltration. Basal levels of CN-1 in serum and urine are genetically determined by the (CTG)n repeat polymorphism and possibly by SNPs within the CNDP1 gene. In normoalbuminuric CKD patients increased urinary CN-1 concentration may reflect increases in renal CN-1 expression and thus may be used as an early biomarker to assess patients at risk for renal function deterioration. By making use of animal models we will assess if the beneficial effect of carnosine is mediated via tubuloglomerular feedback and if carnosine is also protective in a non-diabetic model of glomerulosclerosis. These studies will be complemented with cross-sectional clinical studies to assess the relations between carnosinasuria, CNDP1 genotype and progression of CKD in diabetic and non-diabetic patients. Finally in vitro studies with cultured renal cells will be performed to assess the influence of CNDP1 over-expression.