title: The breakdown of preexisting advanced glycation end products is associated with reduced renal fibrosis in experimental diabetes.
abstract: Renal accumulation of advanced glycation end products (AGEs) has been linked to the progression of diabetic nephropathy. Cleavage of pre-formed AGEs within the kidney by a cross-link breaker, such as ALT-711, may confer renoprotection in diabetes. STZ diabetic rats were randomized into a) no treatment (D); b) treatment with the AGE cross-link breaker, ALT-711, weeks 16-32 (DALT early); and c) ALT-711, weeks 24-32 (DALT late). Treatment with ALT-711 resulted in a significant reduction in diabetes-induced serum and renal AGE peptide fluorescence, associated with decreases in renal carboxymethyllysine and RAGE immunostaining. Cross-linking of tail tendon collagen seen in diabetic groups was attenuated only by 16 weeks of ALT-711 treatment. ALT-711, independent of treatment duration, retarded albumin excretion rate (AER), reduced blood pressure, and renal hypertrophy. It also reduced diabetes-induced increases in gene expression of transforming growth factor beta1 (TGF-beta1), connective tissue growth factor (CTGF), and collagen IV. However, glomerulosclerotic index, tubulointerstitial area, total renal collagen, nitrotyrosine, protein expression of collagen IV, and TGF-beta1 only showed improvement with early ALT treatment alone. This study demonstrates the utility of a cross-link breaker as a treatment for diabetic nephropathy and describes effects not only on renal AGEs but on putative mediators of renal injury, such as prosclerotic cytokines and oxidative stress.
authors.affiliation: Division of Diabetic Complications, Baker Medical Research Institute, Melbourne, Australia. Josephine.forbes@baker.edu.au
authors.forename: Josephine M
authors.initials: JM
authors.lastname: Forbes
authors.forename: Vicki
authors.initials: V
authors.lastname: Thallas
authors.forename: Merlin C
authors.initials: MC
authors.lastname: Thomas
authors.forename: Hank W
authors.initials: HW
authors.lastname: Founds
authors.forename: Wendy C
authors.initials: WC
authors.lastname: Burns
authors.forename: George
authors.initials: G
authors.lastname: Jerums
authors.forename: Mark E
authors.initials: ME
authors.lastname: Cooper
mesh_terms: D000419:Albuminuria / Q000188:drug therapy; D000828:Animal Population Groups; D000818:Animals; D001794:Blood Pressure; D003094:Collagen / Q000737:chemistry / Q000378:metabolism; D055513:Connective Tissue Growth Factor; D003921:Diabetes Mellitus, Experimental / Q000150:complications*; D003928:Diabetic Nephropathies / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D005355:Fibrosis; D017127:Glycation End Products, Advanced / Q000097:blood / Q000378:metabolism*; D017874:Immediate-Early Proteins / Q000096:biosynthesis / Q000235:genetics; D007150:Immunohistochemistry; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis / Q000235:genetics; D007668:Kidney / Q000737:chemistry / Q000473:pathology*; D007700:Kinetics; D008239:Lysine / Q000031:analogs & derivatives* / Q000032:analysis / Q000276:immunology; D008954:Models, Biological; D051381:Rats; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000032:analysis / Q000276:immunology; D012995:Solubility; D013844:Thiazoles / Q000627:therapeutic use*; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000235:genetics; D053773:Transforming Growth Factor beta1; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000032:analysis
chemical_list: C526316:CCN2 protein, rat; D017127:Glycation End Products, Advanced; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; C508962:Tgfb1 protein, rat; D013844:Thiazoles; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D055513:Connective Tissue Growth Factor; C002744:3-nitrotyrosine; D014443:Tyrosine; C048496:N(6)-carboxymethyllysine; D003094:Collagen; C406794:alagebrium; D008239:Lysine