Phosphate feeding induces arterial medial calcification in uremic mice: role of serum phosphorus, fibroblast growth factor-23, and osteopontin.

Arterial medial calcification is a major complication in patients with chronic kidney disease and is a strong predictor of cardiovascular and all-cause mortality. We sought to determine the role of dietary phosphorus and the severity of uremia on vascular calcification in calcification-prone DBA/2 mice. Severe and moderate uremia was induced by renal ablation of varying magnitudes. Extensive arterial-medial calcification developed only when the uremic mice were placed on a high-phosphate diet. Arterial calcification in the severely uremic mice fed a high-phosphate diet was significantly associated with hyperphosphatemia. Moderately uremic mice on this diet were not hyperphosphatemic but had a significant rise in their serum levels of fibroblast growth factor 23 (FGF-23) and osteopontin that significantly correlated with arterial medial calcification. Although there was widespread arterial medial calcification, there was no histological evidence of atherosclerosis. At early stages of calcification, the osteochondrogenic markers Runx2 and osteopontin were upregulated, but the smooth muscle cell marker SM22alpha decreased in medial cells, as did the number of smooth muscle cells in extensively calcified regions. These findings suggest that phosphate loading and the severity of uremia play critical roles in controlling arterial medial calcification in mice. Further, FGF-23 and osteopontin may be markers and/or inducers of this process.

Characterization of mandibular bone in a mouse model of chronic kidney disease.

BACKGROUND: Chronic kidney disease (CKD) is a worldwide health problem with increasing prevalence and poor outcomes, including severe cardiovascular disease and renal osteodystrophy. With advances in medical treatment, patients with CKD are living longer and require oral care. The aim of this study is to determine the effects of CKD and dietary phosphate on mandibular bone structure using a uremic mouse model. METHODS: Uremia (U) was induced in female dilute brown agouti/2 mice by partial renal ablation. Uremic mice received a normal-phosphate (NP) or a high-phosphate (HP) diet. sham surgeries were performed in a control group of mice; half received an NP diet, and the other half was fed an HP diet. At termination, animals were sacrificed, and mandibles were collected for microcomputed tomography (micro-CT) and histologic analysis. RESULTS: Sera levels of blood urea nitrogen, parathyroid hormone, and alkaline phosphatase were significantly increased in U/NP and U/HP mice versus sham controls, whereas serum calcium was increased in the U/HP group, and no differences were noted in serum phosphate levels among groups. Micro-CT analyses revealed a significant reduction in cortical bone thickness and an increase in trabecular thickness and trabecular bone volume/tissue volume in U/NP and U/HP groups compared to the sham/NP group. A significant reduction in cortical bone thickness was also found in the sham/HP group versus the sham/NP group. Histologic evaluation confirmed increased trabeculation in the U groups. CONCLUSION: CKD in mice, especially under conditions of HP feeding, results in marked effects on alveolar bone homeostasis.

N-butyldeoxygalactonojirimycin reduces neonatal brain ganglioside content in a mouse model of GM1 gangliosidosis.

GM1 gangliosidosis is a glycosphingolipid (GSL) lysosomal storage disease caused by a genetic deficiency of acid beta-galactosidase (beta-gal), the enzyme that catabolyzes GM1 within lysosomes. Accumulation of GM1 and its asialo form (GA1) occurs primarily in the brain, leading to progressive neurodegeneration and brain dysfunction. Substrate reduction therapy aims to decrease the rate of GSL biosynthesis to counterbalance the impaired rate of catabolism. The imino sugar N-butyldeoxygalactonojirimycin (NB-DGJ) is a competitive inhibitor of the ceramide-specific glucosyltransferase that catalyzes the first step in GSL biosynthesis. Neonatal C57BL/6J (B6) and beta-gal knockout (-/-) mice were injected daily from post-natal day 2 (p-2) to p-5 with either vehicle or NB-DGJ at 600 mg or 1200 mg/kg body weight. These drug concentrations significantly reduced total brain ganglioside and GM1 content in the B6 and the beta-gal (-/-) mice. Drug treatment had no significant effect on viability, body weight, brain weight, or brain water content in the B6 and beta-gal (-/-) mice. Significant elevations in neutral lipids (GA1, ceramide, and sphingomyelin) were observed in the NB-DGJ-treated beta-gal (-/-) mice, but were not associated with adverse effects. Also, NB-DGJ treatment of B6 and beta-gal (-/-) mice from p-2 to p-5 had no subsequent effect on brain ganglioside content at p-21. Our results show that NB-DGJ is effective in reducing total brain ganglioside and GM1 content at early neonatal ages. These findings suggest that substrate reduction therapy using NB-DGJ may be an effective early intervention for GM1 gangliosidosis and possibly other GSL lysosomal storage diseases.