Effect of Advanced Glycation End-Products (AGE) Lowering Drug ALT-711 on Biochemical, Vascular, and Bone Parameters in a Rat Model of CKD-MBD

Abstract

Chronic kidney disease–mineral bone disorder (CKD‐MBD) is a systemic disorder that affects blood measures of bone and mineral homeostasis, vascular calcification, and bone. We hypothesized that the accumulation of advanced glycation end‐products (AGEs) in CKD may be responsible for the vascular and bone pathologies via alteration of collagen. We treated a naturally occurring model of CKD‐MBD, the Cy/+ rat, with a normal and high dose of the AGE crosslink breaker alagebrium (ALT‐711), or with calcium in the drinking water to mimic calcium phosphate binders for 10 weeks. These animals were compared to normal (NL) untreated animals. The results showed that CKD animals, compared to normal animals, had elevated blood urea nitrogen (BUN), PTH, FGF23 and phosphorus. Treatment with ALT‐711 had no effect on kidney function or PTH, but 3 mg/kg lowered FGF23 whereas calcium lowered PTH. Vascular calcification of the aorta assessed biochemically was increased in CKD animals compared to NL, and decreased by the normal, but not high dose of ALT‐711, with parallel decreases in left ventricular hypertrophy. ALT‐711 (3 mg/kg) did not alter aorta AGE content, but reduced aorta expression of receptor for advanced glycation end products (RAGE) and NADPH oxidase 2 (NOX2), suggesting effects related to decreased oxidative stress at the cellular level. The elevated total bone AGE was decreased by 3 mg/kg ALT‐711 and both bone AGE and cortical porosity were decreased by calcium treatment, but only calcium improved bone properties. In summary, treatment of CKD‐MBD with an AGE breaker ALT‐711, decreased FGF23, reduced aorta calcification, and reduced total bone AGE without improvement of bone mechanics. These results suggest little effect of ALT‐711 on collagen, but potential cellular effects. The data also highlights the need to better measure specific types of AGE proteins at the tissue level in order to fully elucidate the impact of AGEs on CKD‐MBD. © 2019 American Society for Bone and Mineral Research.

Skin Autofluorescence, a Noninvasive Biomarker for Advanced Glycation End-Products, Is Associated With Prevalent Vertebral and Major Osteoporotic Fractures: The Rotterdam Study

“…(53) Moreover, a recent study in CKD rats (n = 56) treated with an AGE breaker, alagebrium, showed reduced total bone AGE content but no difference in bone pentosidine levels, which again points to the heterogeneity in AGEs and limitations of measuring one AGE as a representative of whole group. (54) In sex-stratified analysis for fractures, there was an association of SAF with MOFs only in women but not in men, but no such difference for VFs. Notably in our cohort, the prevalence of MOFs in women is four times higher than in men, which may partly explain this difference.…”

“…( 53 ) Moreover, a recent study in CKD rats ( n = 56) treated with an AGE breaker, alagebrium, showed reduced total bone AGE content but no difference in bone pentosidine levels, which again points to the heterogeneity in AGEs and limitations of measuring one AGE as a representative of whole group. ( 54 )…”

Type I Angiotensin II Receptor Blockade Reduces Uremia-Induced Deterioration of Bone Material Properties

“…Recently, it was reported that reduction of total bone AGE using the AGE cross‐link breaker failed to improve bone mechanical properties in animals with chronic kidney injury. ( 38 ) We assume they failed because AGE accumulation is not the only pathophysiological mechanism underlying deteriorated bone elastic mechanical properties associated with chronic kidney injury, as this study demonstrated.…”

Peroxidasin promotes diabetic vascular endothelial dysfunction induced by advanced glycation end products via NOX2/HOCl/Akt/eNOS pathway

“…Studies show that NOX2 play a critical role in AGEs-induced ROS production and endothelial dysfunction [ 30 , 31 ]. In the present study, we also observed a significant increase of NOX2 expression in the aortas of db/db mice ( Fig.…”