On the relevance of carnosine and carnosinase for the development of diabetic nephropathy

PhD ceremony: Ms. E.M.S. Riedl, 14.30 uur, Aula Academiegebouw, Broerstraat 5, Groningen

Dissertation: On the relevance of carnosine and carnosinase for the development of diabetic nephropathy

Promotor(s): prof. G.J. Navis, prof. B.A. Yard

Faculty: Medical Sciences

A polymorphism in the carnosinase-1-gene (CNDP1) is associated with susceptibility to diabetic nephropathy (DN). The shortest allele, i.e. (CTG)5 (Mannheim-Allele), seems to protect homozygous diabetic patients from DN. The studies presented in this thesis were conducted to find a biological plausibility for this association.

Carnosinase-1 (CN-1) is a glycosylated protein secreted into the serum. We demonstrate that secretion of CN-1 is better when CNDP1 contains a long CTG-repeat, while (CTG)5-encoded CN-1 is poorly secreted. (CTG)5-homozygous individuals therefore have low CN-1 concentrations in serum. Besides, we found that environmental factors influence CN-1 in serum. We provide evidence that hyperglycaemia increases CN-1 secretion by enhancing N-glycosylation leading to elevated CN-1 in (CTG)5-homozygous diabetic patients with poor blood glucose control. Moreover, we show that CN-1 is inhibited by homocarnosine and seems to be present in different ion-dependent conformations.

Several studies have indicated that carnosine, the natural substrate of CN-1, might be a protective factor in DN. We demonstrated that carnosine has anti-fibrotic and cytoprotective properties. Carnosine inhibits extra-cellular-matrix accumulation, influences TGF-β-production/ -signaling and protects diabetic glomeruli from apoptosis and podocyte loss.

In conclusion, the studies described in this thesis demonstrate that CN-1 in serum is determined by the CNDP1 polymorphism. Since low CN-1 in (CTG)5-homozygous patients implicates that more protective carnosine is available, our data might explain why this allele is beneficial. The CNDP1 polymorphism might improve risk-stratification of diabetic patients. However, our data also underscore that environmental factors have to be implemented in such strategies.