title: Carnosine as a protective factor in diabetic nephropathy: association with a leucine repeat of the carnosinase gene CNDP1.
abstract: The risk of diabetic nephropathy is partially genetically determined. Diabetic nephropathy is linked to a gene locus on chromosome 18q22.3-q23. We aimed to identify the causative gene on chromosome 18 and to study the mechanism by which the product of this gene could be involved in the development of diabetic nephropathy. DNA polymorphisms were determined in 135 case (diabetic nephropathy) and 107 control (diabetes without nephropathy) subjects. The effect of carnosine on the production of extracellular matrix components and transforming growth factor-beta (TGF-beta) after exposure to 5 and 25 mmol/l d-glucose was studied in cultured human podocytes and mesangial cells, respectively. A trinucleotide repeat in exon 2 of the CNDP1 gene, coding for a leucine repeat in the leader peptide of the carnosinase-1 precursor, was associated with nephropathy. The shortest allelic form (CNDP1 Mannheim) was more common in the absence of nephropathy (P = 0.0028, odds ratio 2.56 [95% CI 1.36-4.84]) and was associated with lower serum carnosinase levels. Carnosine inhibited the increased production of fibronectin and collagen type VI in podocytes and the increased production of TGF-beta in mesangial cells induced by 25 mmol/l glucose. Diabetic patients with the CNDP1 Mannheim variant are less susceptible for nephropathy. Carnosine protects against the adverse effects of high glucose levels on renal cells.
authors.affiliation: Institute of Human Genetics Heidelberg, Heidelberg, Germany.
authors.forename: Bart
authors.initials: B
authors.lastname: Janssen
authors.forename: Daniela
authors.initials: D
authors.lastname: Hohenadel
authors.forename: Paul
authors.initials: P
authors.lastname: Brinkkoetter
authors.forename: Verena
authors.initials: V
authors.lastname: Peters
authors.forename: Nina
authors.initials: N
authors.lastname: Rind
authors.forename: Christine
authors.initials: C
authors.lastname: Fischer
authors.forename: Ivan
authors.initials: I
authors.lastname: Rychlik
authors.forename: Marie
authors.initials: M
authors.lastname: Cerna
authors.forename: Marianna
authors.initials: M
authors.lastname: Romzova
authors.forename: Emile
authors.initials: E
authors.lastname: de Heer
authors.forename: Hans
authors.initials: H
authors.lastname: Baelde
authors.forename: Stephan J L
authors.initials: SJ
authors.lastname: Bakker
authors.forename: Mahmoud
authors.initials: M
authors.lastname: Zirie
authors.forename: Eric
authors.initials: E
authors.lastname: Rondeau
authors.forename: Peter
authors.initials: P
authors.lastname: Mathieson
authors.forename: Moin A
authors.initials: MA
authors.lastname: Saleem
authors.forename: Jochen
authors.initials: J
authors.lastname: Meyer
authors.forename: Hannes
authors.initials: H
authors.lastname: Köppel
authors.forename: Sibylle
authors.initials: S
authors.lastname: Sauerhoefer
authors.forename: Claus R
authors.initials: CR
authors.lastname: Bartram
authors.forename: Peter
authors.initials: P
authors.lastname: Nawroth
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Hammes
authors.forename: Benito A
authors.initials: BA
authors.lastname: Yard
authors.forename: Johannes
authors.initials: J
authors.lastname: Zschocke
authors.forename: Fokko J
authors.initials: FJ
authors.lastname: van der Woude
mesh_terms: D000368:Aged; D002336:Carnosine / Q000494:pharmacology / Q000502:physiology*; D002478:Cells, Cultured; D003922:Diabetes Mellitus, Type 1; D003924:Diabetes Mellitus, Type 2; D003928:Diabetic Nephropathies / Q000235:genetics / Q000517:prevention & control*; D004150:Dipeptidases / Q000097:blood / Q000235:genetics*; D005260:Female; D015870:Gene Expression; D020022:Genetic Predisposition to Disease; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D007668:Kidney / Q000737:chemistry; D007930:Leucine; D008297:Male; D008875:Middle Aged; D012333:RNA, Messenger / Q000032:analysis; D020449:Repetitive Sequences, Amino Acid; D016415:Sequence Alignment
chemical_list: D012333:RNA, Messenger; D002336:Carnosine; D004150:Dipeptidases; C019673:aminoacyl-histidine dipeptidase; D007930:Leucine; D005947:Glucose