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J Bone Miner Res. 2019 Nov 19. doi: 10.1002/jbmr.3925. [Epub ahead of print]

Effect of advanced glycation end-products (AGE) lowering drug ALT-711 on biochemical, vascular, and bone parameters in a rat model of CKD-MBD.

Author information

1
Division of Nephrology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
2
Division of Nephrology, Department of Medicine, Columbia University Medical Center, New York, NY, USA.
3
Department of Biomedical Engineering, Indiana University-Purdue University at Indianapolis, Indianapolis, IN, USA.
4
Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN, USA.
5
Department of Physical Therapy, Indiana University School of Health and Rehabilitation Sciences, Indianapolis, IN, USA.

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 (AGE) 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 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. This article is protected by copyright. All rights reserved.

KEYWORDS:

Bone QCT/μCT; bone quality; chronic kidney disease-mineral bone disorder (CKD-MBD); vascular calcification

PMID:
31743501
DOI:
10.1002/jbmr.3925

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