The breakdown of preexisting advanced glycation end products is associated with reduced renal fibrosis in experimental diabetes.
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.
Forbes
Josephine M
JM
Division of Diabetic Complications, Baker Medical Research Institute, Melbourne, Australia. Josephine.forbes@baker.edu.au
Thallas
Vicki
V
Thomas
Merlin C
MC
Founds
Hank W
HW
Burns
Wendy C
WC
Jerums
George
G
Cooper
Mark E
ME
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
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