title: Temporal increases in urinary carboxymethyllysine correlate with albuminuria development in diabetes.
abstract: OBJECTIVE
  Advanced glycation end products (AGEs) mediate progressive tissue damage in diabetic nephropathy; however, their utility as a noninvasive reliable biomarker of progressive diabetic nephropathy remains to be determined. In this study, we investigated the temporal accumulation of the AGE carboxymethyllysine (CML) at various sites in a model of experimental diabetic nephropathy.
  
  
  METHODS
  Diabetic rats were followed for 1, 4, 8, 16 and 32 weeks. Glomerular filtration rate and urinary albumin excretion were measured. CML was determined in the plasma, urine, renal cortical mitochondria and cytosol by an in-house ELISA. Gene expression of AGE receptors were quantified by real-time PCR and urinary excretion of 8-hydroxy-2'-deoxyguanosine (8-OHdG) was determined by EIA.
  
  
  RESULTS
  Four weeks after diabetes induction, urinary CML excretion was increased, which preceded the excretion of urinary albumin and continued to rise progressively until 32 weeks. Circulating, mitochondrial and cytosolic CML content and urinary excretion of 8-OHdG were increased 4 weeks after diabetes induction, but did not increase further with diabetes duration. Renal gene expression of AGE receptors was transiently upregulated at 1 week of diabetes, but this was not a sustained phenomenon.
  
  
  CONCLUSIONS
  The most informative marker of progressive renal damage linked to the AGE pathway in experimental diabetic nephropathy is urinary excretion of CML, which now warrants clinical investigation as a potential noninvasive sensitive marker of progressive diabetic nephropathy.
authors.affiliation: Glycation and Diabetes Complications Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne, VIC, Australia. Melinda.Coughlan@bakeridi.edu.au
authors.forename: Melinda T
authors.initials: MT
authors.lastname: Coughlan
authors.forename: Josephine M
authors.initials: JM
authors.lastname: Forbes
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D000419:Albuminuria / Q000652:urine; D000818:Animals; D015415:Biomarkers / Q000097:blood / Q000652:urine; D003600:Cytosol / Q000378:metabolism; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000652:urine; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000139:chemically induced / Q000378:metabolism*; D003928:Diabetic Nephropathies / Q000235:genetics / Q000378:metabolism* / Q000652:urine; D015870:Gene Expression; D005919:Glomerular Filtration Rate; D017127:Glycation End Products, Advanced / Q000378:metabolism* / Q000652:urine; D007672:Kidney Cortex / Q000378:metabolism*; D008239:Lysine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000652:urine; D008297:Male; D008928:Mitochondria / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000235:genetics* / Q000378:metabolism; D013311:Streptozocin; D013997:Time Factors
chemical_list: D015415:Biomarkers; D017127:Glycation End Products, Advanced; D012333:RNA, Messenger; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D013311:Streptozocin; C048496:N(6)-carboxymethyllysine; D000080242:8-Hydroxy-2'-Deoxyguanosine; D003849:Deoxyguanosine; D008239:Lysine