Nami Kobayashi

Cinacalcet suppresses calcification of the aorta and heart in uremic rats

High serum parathyroid hormone levels are associated with vascular calcification. Cinacalcet is a calcimimetic agent that inhibits parathyroid hormone secretion and is used to treat patients with secondary hyperparathyroidism. Here we measured the effects of oral cinacalcet on calcification of the aorta and heart in rats with a remnant kidney (5/6 nephrectomy) model of uremia that were fed a high-phosphate diet containing lactose to accelerate the process of aortic calcification. Alizarin red staining showed that the smooth muscle in the aortic arch of rats with a remnant kidney was calcified. The tissue levels of calcium and phosphorus in the aorta and hearts of these rats were significantly increased compared to sham-operated rats. Expression of the osteoblastic lineage genes osteocalcin, osteopontin and runt-related gene 2 were also increased in the aorta of these rats. Cinacalcet suppressed these calcification-related changes by reducing serum parathyroid hormone, calcium, phosphorus, and the calcium-phosphorus product. Parathyroidectomy also suppressed calcification in this model. We suggest that cinacalcet inhibits calcification of the aorta and heart in uremic patients with secondary hyperparathyroidism by decreasing serum parathyroid hormone levels.

Beneficial Effects of a Novel Inhibitor of Platelet-Derived Growth Factor Receptor Autophosphorylation in the Rat with Mesangial Proliferative Glomerulonephritis

1. Our original compound, Ki6896 ((4-t-butylphenyl)(4-[(6,7-dimethoxy-4-quinolyl) oxy]phenyl) methanone) strongly inhibited the autophosphorylation of platelet-derived growth factor (PDGF) beta-receptor (IC50=0.31 microM) and that of basic fibroblast growth factor receptor (IC50=3.1 microM), whereas it did not inhibit some other kinases. 2. The [3H]thymidine incorporation and the growth of mesangial cells under the stimulation of PDGF were inhibited by Ki6896 in a dose-dependent manner. 3. In the mesangial proliferative glomerulonephritis rats induced by anti-Thy-1 monoclonal antibody, glomerulosclerosis was ameliorated and the number of glomerular proliferating cells was decreased by the daily administration of Ki6896. However, the accumulation of type I collagen and fibronectin in the glomeruli was not suppressed by Ki6896.

Effects of Chitosan-Coated Dialdehyde Cellulose, a Newly Developed Oral Adsorbent, on Glomerulonephritis Induced by Anti-Thy-1 Antibody in Rats

The effects of chitosan-coated dialdehyde cellulose (chitosan DAC), a newly developed oral adsorbent for urea and ammonia, were examined in a glomerulonephritis model in rats. Mesangial proliferative glomerulonephritis accompanied with proteinuria was induced by an intravenous injection of anti-rat Thy-1.1 monoclonal antibody (OX-7). The proliferation of mesangial cells and an accumulation of extracellular matrix components such as type I collagen and fibronectin were observed in the glomeruli 9 days after OX-7 injection; these were improved in rats fed a diet containing chitosan DAC (10% content) for 9 days compared with those in rats fed a normal diet. Chitosan DAC treatment decreased the elevated urinary protein and blood urea nitrogen at days 8–9 to the normal levels; the increased fecal excretion of nitrogen might participate in this phenomenon. In addition, chitosan DAC treatment showed an increase in fecal water content associated with a decrease in urinary volume. These therapeutic effects may be due to the reduction of proteinic factor expression and the compensational function of chitosan DAC for kidney. These results suggest that chitosan DAC treatment may be useful for ameliorating mesangial proliferative glomerulonephritis.