Cathepsins D and L reduce the toxicity of advanced glycation end products

Free Radic Biol Med. 2012 Mar 15;52(6):1011-23. doi: 10.1016/j.freeradbiomed.2011.12.021. Epub 2012 Jan 4.


Advanced glycation end product-modified proteins are known for accumulating during aging and in several pathological conditions such as diabetes, renal failure, and neurodegenerative disorders. There is little information about the intracellular fate of endocytosed advanced glycation end products (AGEs) and their influence on proteolytic systems. However, it is known that the lysosomal system is impaired during aging. Therefore, undegraded material may accumulate and play a considerable role in the development of diverse diseases. To investigate if AGEs can be degraded and to test whether they accumulate because of impaired lysosomal proteases we studied the effects of advanced glycation end products on the endosomal-lysosomal system. Five different types of AGEs were generated by bovine serum albumin incubation with glyoxal, methylglyoxal, glucose, fructose, and ribose. The first experiments revealed the uptake of AGEs by the macrophage cell line RAW 264.7. Further investigations demonstrated an increase in cathepsin D and L activity and an increase in mature cathepsins D and L. Increased activities were accompanied by the presence of more lysosomes, measured by staining with LysoTracker blue. To specify the roles of cathepsins D and L we used knockout cells to test the roles of both cathepsins on the toxicity of advanced glycation end products. In summary we conclude that both cathepsins are required for a reduction in advanced glycation end product-induced cytotoxicity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cathepsin D / genetics
  • Cathepsin D / metabolism*
  • Cathepsin L / genetics
  • Cathepsin L / metabolism*
  • Cattle
  • Cell Line
  • Diabetes Mellitus / metabolism*
  • Enzyme Activation / drug effects
  • Gene Knockout Techniques
  • Glycation End Products, Advanced / chemistry
  • Glycation End Products, Advanced / pharmacology
  • Humans
  • Lysosomes / drug effects
  • Lysosomes / pathology
  • Macrophages / drug effects*
  • Macrophages / metabolism
  • Macrophages / pathology
  • Mice
  • Monosaccharides / chemistry
  • Monosaccharides / pharmacology
  • Neurodegenerative Diseases / metabolism*
  • Proteolysis / drug effects
  • Renal Insufficiency / metabolism*
  • Serum Albumin, Bovine / chemistry
  • Serum Albumin, Bovine / pharmacology


  • Glycation End Products, Advanced
  • Monosaccharides
  • Serum Albumin, Bovine
  • Cathepsin L
  • Cathepsin D