Effect of Advanced Glycation End-Products (AGE) Lowering Drug ALT-711 on Biochemical, Vascular, and Bone Parameters in a Rat Model of CKD-MBD.
BONE QCT/μCT
BONE QUALITY
CHRONIC KIDNEY DISEASE-MINERAL BONE DISORDER (CKD-MBD)
VASCULAR CALCIFICATION
Journal
Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research
ISSN: 1523-4681
Titre abrégé: J Bone Miner Res
Pays: United States
ID NLM: 8610640
Informations de publication
Date de publication:
03 2020
03 2020
Historique:
received:
29
04
2019
revised:
04
11
2019
pubmed:
20
11
2019
medline:
29
7
2021
entrez:
20
11
2019
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 31743501
doi: 10.1002/jbmr.3925
pmc: PMC9030558
mid: NIHMS1703790
doi:
Substances chimiques
Minerals
0
Pharmaceutical Preparations
0
Thiazoles
0
alagebrium
DGH49JXB1F
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
608-617Subventions
Organisme : NIDDK NIH HHS
ID : K08 DK110429
Pays : United States
Organisme : NIAMS NIH HHS
ID : K25 AR067221
Pays : United States
Organisme : NIAMS NIH HHS
ID : T32 AR065971
Pays : United States
Organisme : BLRD VA
ID : I01 BX003025
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR002529
Pays : United States
Organisme : NIDDK NIH HHS
ID : T32 DK120524
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK110871
Pays : United States
Organisme : BLRD VA
ID : I01 BX001471
Pays : United States
Informations de copyright
© 2019 American Society for Bone and Mineral Research.
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