Identification of CML-modified Proteins in Hemofiltrate of Diabetic Patients by Proteome Analysis

S. Schmitt; M. Linder; L. Ständker; H.-P. Hammes; K. T. Preissner

doi:10.1055/s-2007-985370

Experimental and Clinical Endocrinology & Diabetes, Inhaltsverzeichnis

Exp Clin Endocrinol Diabetes 2008; 116(1): 26-34
DOI: 10.1055/s-2007-985370

Article

Identification of CML-modified Proteins in Hemofiltrate of Diabetic Patients by Proteome Analysis

S. Schmitt¹ , M. Linder¹ , L. Ständker³ , H.-P. Hammes² , K. T. Preissner¹

¹Department of Biochemistry, Justus-Liebig-University, Medical Faculty, Giessen, Germany
²5th Medical Clinic, University-Hospital Mannheim, Ruprecht-Karls-University, Medical Faculty, Heidelberg, Germany
³Hannover Medical School, Center of Pharmacology, Hannover, Germany

Abstract

The posttranslational modification of extra- and intracellular proteins by non-enzymatic glycation results in the formation of advanced glycation end products (AGEs) in physiological systems and is associated with the loss of protein structure and function. Modification by N^ε-carboxymethyl lysine (CML) correlates with the risk for retinopathy in diabetes mellitus and has been discussed as a marker for the prediction of mortality in hemodialysis patients. AGEing of proteins is particularly increased under hyperglycemia associated with different late complications of diabetes mellitus. Modification of proteins to form AGE residues is significantly more enhanced in patients suffering from chronic renal disease than in hyperglycemia and is associated with increased risk for cardiovascular complications and inflammation in patients with chronic renal insuffiency. In order to identify and define the protein “substrates” for non-enzymatic glycation we used a proteome approach combining two-dimensional gel electrophoresis and immunoblotting with Edman protein sequencing to identify specific CML-modified proteins in human hemofiltrate, which essentially resembles plasma with respect to protein composition. Albumin, Ig kappa chain, prostaglandin D2 synthase, lysozyme C, plasma retinol binding protein and beta-2-microglobulin were identified as the major CML-modified proteins. CML-modified fragments of these proteins were also found in hemofiltrate. All identified proteins have in common that they appeared in hemofiltrate predominantly in their CML-modified form(s). Further studies of the functional roles of proteins identified by this new experimental approach could lead to the development of diagnostic tools to follow the progression of diabetes and contribute to the understanding of the pathogenesis of AGE-related diseases.

Key words

advanced glycation end products - N^ε-carboxymethyl lysine - proteomics - diabetes mellitus - renal insuffiency - hemofiltrate - two-dimensional gel electrophoresis

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Correspondence

K.T. PreissnerPhD

Department of Biochemistry

Justus-Liebig-University

Medical Faculty

Friedrichstrasse 24

35392 Giessen

Germany

Telefon: +49/641/99 47 50 0

Fax: +49/641/99 47 50 9

eMail: Klaus.T.Preissner@biochemie.med.uni-giessen.de