Abstract 505: An Iron Chelator, Deferasirox, Prevents Renal Iron Accumulation and Macrophage Infiltration But Not Cell Senescence in Type 1 Diabetic Mice
We previously reported that streptozotocin (STZ)-induced type 1 diabetes caused renal tubular cell senescence through blood glucose- and p21-dependent pathway at week 4 of STZ administration in mice. We investigated the involvement of the cell senescence on accumulation of iron in the renal tubular cells in the present study. STZ mice (n=5) did not show the significant iron accumulation in the kidney at week 4. STZ mice (n=10) showed increases in renal tubular iron accumulation (Perl’s Prussian blue: 278.1±71.9 fold vs. non-diabetic control, p<0.01), F4/80-positive macrophage infiltration (2.6±0.6 fold vs. non-diabetic control, p<0.01), and cell senescence (senescence-associated β galactosidase: 3.7±0.4 fold, p16 mRNA: 2.3±0.2 fold vs. non-diabetic control, respectively, p<0.01, respectively) at week 28. Administering oral iron chelator, deferasirox (10 mg/kg/day, n=10), that removes only dietary iron, significantly attenuated the iron accumulation (38.1±12.4 fold vs. non-diabetic control, n.s.) in proximal tubules and the F4/80-positive cells number (1.3±0.3 fold, vs. non-diabetic control, n.s.) without the effect on blood glucose, hematocrit and hemoglobin levels. On the other hand, deferasirox did not affect renal cell senescence (senescence-associated β galactosidase: 3.9±0.5 fold, p16 mRNA: 2.4±0.3 fold vs. non-diabetic control, respectively, n.s.). The functional deletion of p21, a cyclin-dependent kinase inhibitor, in mice decreased the renal tubular iron accumulation (14.0±5.5 fold vs. non-diabetic control, p<0.01), and did not change the cell senescence at week 28. The animals showed an increase in p16, another cyclin-dependent kinase inhibitor, suggesting that p16 rather than p21 plays important role on cell senescence in the kidney of STZ mice at this time point. The results indicate that the chelation of dietary iron attenuates renal iron accumulation and macrophage infiltration through p21-dependent pathway in STZ mice. It seems likely that there is little interaction between renal tubular cell senescence and iron accumulation in the type 1 diabetic kidney.
- © 2013 by American Heart Association, Inc.