Carnosine as a Protective Factor in Diabetic Nephropathy

Association With a Leucine Repeat of the Carnosinase Gene CNDP1

  1. Bart Janssen1,
  2. Daniela Hohenadel2,
  3. Paul Brinkkoetter2,
  4. Verena Peters3,
  5. Nina Rind1,
  6. Christine Fischer1,
  7. Ivan Rychlik4,
  8. Marie Cerna4,
  9. Marianna Romzova4,
  10. Emile de Heer5,
  11. Hans Baelde5,
  12. Stephan J.L. Bakker6,
  13. Mahmoud Zirie7,
  14. Eric Rondeau8,
  15. Peter Mathieson9,
  16. Moin A. Saleem9,
  17. Jochen Meyer1,
  18. Hannes Köppel2,
  19. Sibylle Sauerhoefer2,
  20. Claus R. Bartram1,
  21. Peter Nawroth10,
  22. Hans-Peter Hammes2,
  23. Benito A. Yard2,
  24. Johannes Zschocke1 and
  25. Fokko J. van der Woude2
  1. 1Institute of Human Genetics Heidelberg, Heidelberg, Germany
  2. 2Department of Nephrology, Endocrinology and Rheumatology, Fifth Medical Clinic, Mannheim, Germany
  3. 3First Department of Pediatrics, University Hospital Heidelberg, Heidelberg, Germany
  4. 4Second Department of Medicine and Departement of Cell and Molecular Biology, Third Faculty of Medicine, Charles University, Prague, Czech Republic
  5. 5Department of Pathology, Leiden University Medical Centre, Leiden, the Netherlands
  6. 6Department of Internal Medicine, University Medical Centre Groningen, Groningen, the Netherlands
  7. 7Hamad Medical Corporation, Doha, Qatar
  8. 8Service de Nephrologie A, Hopital Tenon, Institut National de la Santé et de la Recherche Medicalé, Paris, France
  9. 9Academic Renal Unit, Southmead Hospital, Bristol, U.K
  10. 10Department of Endocrinology and Nephrology, Third Medical Clinic, Heidelberg, Germany
  1. Address correspondence and reprint requests to Prof. Dr. Fokko J. van der Woude, Fifth Medical University Clinic Klinikum Mannheim, Theodor-Kutzer-Ufer 1-3 D-68135, Germany. E-mail: fokko.van-der-woude{at}med5.ma.uni-heidelberg.de

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-β (TGF-β) 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-β 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.

Footnotes

  • B.J., D.H., and P.B. contributed equally to this study.

    • Accepted May 9, 2005.
    • Received March 22, 2005.
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