The breakdown of pre‐existing 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.

Delayed intervention with AGE inhibitors attenuates the progression of diabetes-accelerated atherosclerosis in diabetic apolipoprotein E knockout mice

“…In our study, delayed intervention with alagebrium was associated with a significant attenuation of oxidative stress in the vascular wall, as measured by accumulation of nitrotyrosine residues. By contrast, it has previously been found that alagebrium, 10 mg kg −1 per day −1 , did not decrease renal nitrotyrosine staining in the kidney of diabetic rats when given as a delayed intervention [18].…”

Advanced glycation of apolipoprotein A-I impairs its anti-atherogenic properties

“…First, we used the putative AGE crosslink breaker alagebrium chloride (ALT-711) [26]. When AGE-modified apoA-I was pretreated with 0.1 mg/ml alagebrium chloride, its ability to support cholesterol efflux was fully restored (Fig.…”

A developmental nephron deficit in rats is associated with increased susceptibility to a secondary renal injury due to advanced glycation end-products

“…Collagen-associated AGE fluorescence was determined in 24-h acid-hydrolysed collagen preparations following sequential extractions with 1.0 mol/l NaCl, 0.5 mol/l acetic acid and delipidation with chloroform:methanol (1:2) by flow injection, as described above [25]. To correct for differences in the collagen content of samples, fluorescence intensity was expressed as the percentage of fluorescence per mg renal collagen.…”